Imidazotriazines as protein kinase inhibitors

ABSTRACT

Compounds of the formula 
                         
and pharmaceuticaly acceptable salts thereof, wherein Q 1  and R 1  are defined herein, inhibit the IGF-1R enzyme and are useful for the treatment and/or prevention of various diseases and conditions that respond to treatment by inhibition of tyrosine kinases.

This application claims the benefit of U.S. Provisional Application No.60/589,514, filed Jul. 20, 2004.

BACKGROUND OF THE INVENTION

The present invention is directed to novel imidazotriazine compounds,their salts, and compositions comprising them. In particular, thepresent invention is directed to novel imidazotriazine compounds thatinhibit the activity of tyrosine kinase enzymes in animals, includinghumans, for the treatment and/or prevention of various diseases andconditions such as cancer.

Protein tyrosine kinases (PTKs) are enzymes that catalyse thephosphorylation of specific tyrosine residues in various cellularproteins involved in regulation of cell proliferation, activation, ordifferentiation (Schlessinger and Ullrich, 1992, Neuron 9:383-391).Aberrant, excessive, or uncontrolled PTK activity has been shown toresult in uncontrolled cell growth and has been observed in diseasessuch as benign and malignant proliferative disorders, as well as havingbeen observed in diseases resulting from an inappropriate activation ofthe immune system (e.g., autoimmune disorders), allograft rejection, andgraft vs. host disease. In addition, endothelial-cell specific receptorPTKs such as KDR and Tie-2 mediate the angiogenic process, and are thusinvolved in supporting the progression of cancers and other diseasesinvolving inappropriate vascularization (e.g., diabetic retinopathy,choroidal neovascularization due to age-related macular degeneration,psoriasis, arthritis, retinopathy of prematurity, infantilehemangiomas).

Tyrosine kinases can be of the receptor-type (having extracellular,transmembrane and intracellular domains) or the non-receptor type (beingwholly intracellular). The Receptor Tyrosine Kinases (RTKs) comprise alarge family of transmembrane receptors with at least nineteen distinctRTK subfamilies having diverse biological activities. The RTK familyincludes receptors that are crucial for the growth and differentiationof a variety of cell types (Yarden and Ullrich, Ann. Rev. Biochem.57:433-478, 1988; Ullrich and Schlessinger, Cell 61:243-254, 1990). Theintrinsic function of RTKs is activated upon ligand binding, whichresults in phosphorylation of the receptor and multiple cellularsubstrates, and subsequently results in a variety of cellular responses(Ullrich & Schlessinger, 1990, Cell 61:203-212). Thus, RTK mediatedsignal transduction is initiated by extracellular interaction with aspecific growth factor (ligand), typically followed by receptordimerization, stimulation of the intrinsic protein tyrosine kinaseactivity and receptor trans-phosphorylation. Binding sites are therebycreated for intracellular signal transduction molecules and lead to theformation of complexes with a spectrum of cytoplasmic signalingmolecules that facilitate a corresponding cellular response such as celldivision, differentiation, metabolic effects, and changes in theextracellular microenvironment (Schlessinger and Ullrich, 1992, Neuron9:1-20).

Malignant cells are associated with the loss of control over one or morecell cycle elements. These elements range from cell surface receptors tothe regulators of transcription and translation, including theinsulin-like growth factors, insulin growth factor-I (IGF-1) and insulingrowth factor-2 (IGF-2) (M. J. Ellis, “The Insulin-Like Growth FactorNetwork and Breast Cancer”, Breast Cancer, Molecular Genetics,Pathogenesis and Therapeutics, Humana Press 1999). The insulin growthfactor system consists of families of ligands, insulin growth factorbinding proteins, and receptors.

A major physiological role of the IGF-1 system is the promotion ofnormal growth and regeneration. Overexpressed IGF-1R (type 1insulin-like growth factor receptor) can initiate mitogenesis andpromote ligand-dependent neoplastic transformation. Furthermore, IGF-1Rplays an important role in the establishment and maintenance of themalignant phenotype.

IGF-1R exists as a heterodimer, with several disulfide bridges. Thetyrosine kinase catalytic site and the ATP binding site are located onthe cytoplasmic portion of the beta subunit. Unlike the epidermal growthfactor (EGF) receptor, no mutant oncogenic forms of the IGF-1R have beenidentified. However, several oncogenes have been demonstrated to affectIGF-1 and IGF-1R expression. The correlation between a reduction ofIGF-1R expression and resistance to transformation has been seen.Exposure of cells to the mRNA antisense to IGF-1R RNA prevents soft agargrowth of several human tumor cell lines.

Apoptosis is a ubiquitous physiological process used to eliminatedamaged or unwanted cells in multicellular organisms. Misregulation ofapoptosis is believed to be involved in the pathogenesis of many humandiseases. The failure of apoptotic cell death has been implicated invarious cancers, as well as autoimmune disorders. Conversely, increasedapoptosis is associated with a variety of diseases involving cell losssuch as neurodegenerative disorders and AIDS. As such, regulators ofapoptosis have become an important therapeutic target. It is nowestablished that a major mode of tumor survival is escape fromapoptosis. IGF-1R abrogates progression into apoptosis, both in vivo andin vitro. It has also been shown that a decrease in the level of IGF-1Rbelow wild-type levels causes apoptosis of tumor cells in vivo. Theability of IGF-1R disruption to cause apoptosis appears to be diminishedin normal, non-tumorigenic cells.

Inappropriately high protein kinase activity has been implicated in manydiseases resulting from abnormal cellular function. This might ariseeither directly or indirectly by a failure of the proper controlmechanisms for the kinase, related to mutation, over-expression orinappropriate activation of the enzyme; or by an over- orunderproduction of cytokines or growth factors participating in thetransduction of signals upstream or downstream of the kinase. In all ofthese instances, selective inhibition of the action of the kinase mightbe expected to have a beneficial effect.

IGF-1R is a transmembrane RTK that binds primarily to IGF-1 but also toIGF-II and insulin with lower affinity. Binding of IGF-1 to its receptorresults in receptor oligomerization, activation of tyrosine kinase,intermolecular receptor autophosphorylation and phosphorylation ofcellular substrates (major substrates are IRS1 and Shc). Theligand-activated IGF-1R induces mitogenic activity in normal cells andplays an important role in abnormal growth.

The IGF-1 pathway in human tumor development has an important role: 1)IGF-1R overexpression is frequently found in various tumors (breast,colon, lung, sarcoma) and is often associated with an aggressivephenotype. 2) High circulating IGF1 concentrations are stronglycorrelated with prostate, lung and breast cancer risk Furthermore,IGF-1R is required for establishment and maintenance of the transformedphenotype in vitro and in vivo (Baserga R. Exp. Cell. Res., 1999, 253,1-6). The kinase activity of IGF-1R is essential for the transformingactivity of several oncogenes: EGFR, PDGFR, SV40 T antigen, activatedRas, Raf, and v-Src. The expression of IGF-1R in normal fibroblastsinduces neoplastic phenotypes, which can then form tumors in vivo.IGF-1R expression plays an important role in anchorage-independentgrowth. IGF-1R has also been shown to protect cells from chemotherapy-,radiation-, and cytoline-induced apoptosis. Conversely, inhibition ofendogenous IGF-1R by dominant negative IGF-1R, triple helix formation orantisense expression vector has been shown to repress transformingactivity in vitro and tumor growth in animal models.

Many of the tyrosine kinases, whether an RTK or non-receptor tyrosinekinase, have been found to be involved in cellular signaling pathwaysinvolved in numerous disorders, including cancer, psoriasis, fibrosis,atherosclerosis, restenosis, auto-immune disease, allergy, asthma,transplantation rejection, inflammation, thrombosis, nervous systemdiseases, and other hyperproliferative disorders or hyper-immuneresponses. It is desirable to provide novel inhibitors of kinasesinvolved in mediating or maintaining disease states to treat suchdiseases.

The identification of effective small compounds that specificallyinhibit signal transduction and cellular proliferation, by modulatingthe activity of receptor and non-receptor tyrosine and serine/threoninekinases, to regulate and modulate abnormal or inappropriate cellproliferation, differentiation, or metabolism is therefore desirable. Inparticular, the identification of methods and compounds thatspecifically inhibit the function of a tyrosine kinase essential forangiogenic processes or for the formation of vascular hyperpermeabilityleading to edema, ascites, effusions, exudates, macromolecularextravasation, matrix deposition, and their associated disorders wouldbe beneficial.

It has been recognized that inhibitors of protein-tyrosine kinases areuseful as selective inhibitors of the growth of mammalian cancer cells.For example, Gleevec™ (also known as imatinib mesylate, or STI571), a2-phenylpyrimidine tyrosine kinase inhibitor that inhibits the kinaseactivity of the BCR-ABL fusion gene product, was recently approved bythe U.S. Food and Drug Administration for the treatment of CML. Thiscompound, in addition to inhibiting BCR-ABL kinase, also inhibits KITkinase and PDGF receptor kinase, although it is not effective againstall mutant isoforms of KIT kinase. In recent clinical studies on the useof Gleevec™ to treat patients with GIST, a disease in which KIT kinaseis involved in transformation of the cells, many of the patients showedmarked clinical improvement. Other kinase inhibitors show even greaterselectively. For example, the 4-anilinoquinazoline compound Tarceva™inhibits only EGF receptor kinase with high potency, although it caninhibit the signal transduction of other receptor kinases, probablybecause such receptors heterodimerize with the EGF receptor.

In view of the importance of PTKs to the control, regulation, andmodulation of cell proliferation and the diseases and disordersassociated with abnormal cell proliferation, many attempts have beenmade to identify small molecule tyrosine kinase inhibitors. Bis-,mono-cyclic, bicyclic or heterocyclic aryl compounds (InternationalPatent Publication No. WO 92/20642) and vinylene-azaindole derivatives(International Patent Publication No. WO 94/14808) have been describedgenerally as tyrosine kinase inhibitors. Styryl compounds (U.S. Pat. No.5,217,999), styryl-substituted pyridyl compounds (U.S. Pat. No.5,302,606), certain quinazoline derivatives (EP Application No. 0566266A1; Expert Opin. Ther. Pat. (1998), 8(4): 475-478), selenoindoles andselenides (International Patent Publication No. WO 94/03427), tricyclicpolyhydroxylic compounds (International Patent Publication No. WO92/21660) and benzylphosphonic acid compounds (International PatentPublication No. WO 91/15495) have been described as compounds for use astyrosine kinase inhibitors for use in the treatment of cancer.Anilinocinnolines (PCT WO97/34876) and quinazoline derivative compounds(International Patent Publication No. WO 97/22596; International PatentPublication No. WO97/42187) have been described as inhibitors ofangiogenesis and vascular permeability. Bis(indolylmaleimide) compoundshave been described as inhibiting particular PKC serine/threonine kinaseisoforms whose signal transducing function is associated with alteredvascular permeability in VEGF-related diseases (International PatentPublication Nos. WO 97/40830 and WO 97/40831).

International Patent Publication Nos. WO 03/018021 and WO 03/018022describe pyrimidines for treating IGF-1R related disorders,International Patent Publication Nos. WO 02/102804 and WO 02/102805describe cyclolignans and cyclolignans as IGF-1R inhibitors,International Patent Publication No. WO 02/092599 describespyrrolopyrimidines for the treatment of a disease which responds to aninhibition of the IGF-1R tyrosine kinase, International PatentPublication No. WO 01/72751 describes pyrrolopyrimidines as tyrosinekinase inhibitors. International Patent Publication No. WO 00/71129describes pyrrolotriazine inhibitors of kinases. International PatentPublication No. WO 97/28161 describes pyrrolo [2,3-d]pyrimidines andtheir use as tyrosine kinase inhibitors.

Parrizas, et al. describes tyrphostins with in vitro and in vivo IGF-1Rinhibitory activity (Endocrinology, 138:1427-1433 (1997)), andInternational Patent Publication No. WO 00/35455 describesheteroaryl-aryl ureas as IGF-1R inhibitors. International PatentPublication No. WO 03/048133 describes pyrimidine derivatives asmodulators of IGF-1R. International Patent Publication No. WO 03/024967describes chemical compounds with inhibitory effects towards kinaseproteins. International Patent Publication No. WO 03/068265 describesmethods and compositions for treating hyperproliferative conditions.International Patent Publication No. WO 00/17203 describespyrrolopyrimidines as protein kinase inhibitors. Japanese PatentPublication No. JP 07/133280 describes a cephem compound, its productionand antimicrobial composition. A. Albert et al., Journal of the ChemicalSociety, 11: 1540-1547 (1970) describes pteridine studies and pteridinesunsubstituted in the 4-position, a synthesis from pyrazines via3,4-dhydropteridines. A. Albert et al., Chem. Biol. Pteridines Proc.Int. Symp., 4th, 4: 1-5 (1969) describes a synthesis of pteridines(unsubstituted in the 4-position) from pyrazines, via3-4-dihydropteridines.

IGF-1R performs important roles in cell division, development, andmetabolism, and in its activated state, plays a role in oncogenesis andsuppression of apoptosis. IGF-1R is known to be overexpressed in anumber of cancer cell lines (IGF-1R overexpression is linked toacromegaly and to cancer of the prostate). By contrast, down-regulationof IGF-1R expression has been shown to result in the inhibition oftumorigenesis and an increased apoptosis of tumor cells.

Although the anticancer compounds described above have made asignificant contribution to the art, there is a continuing need in thisfield of art to improve anticancer pharmaceuticals with betterselectivity or potency, reduced toxicity, or fewer side effects.

SUMMARY OF THE INVENTION

The present invention relates to compounds of Formula I:

or a pharmaceutically acceptable salt thereof. The compounds of FormulaI inhibit the IGF-1R enzyme and are useful for the treatment and/orprevention of various diseases and conditions that respond to treatmentby inhibition of IGF-1R. In particular, compounds of this invention areuseful as inhibitors of tyrosine kinases that are important inhyperproliferative diseases, especially cancer.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Q¹ is aryl¹, heteroaryl¹, cycloC₃₋₁₀alkyl, heterocyclyl,cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which is optionallysubstituted by one to five independent G¹⁰ substituents;

R¹ is C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, heterocyclyl, or heterobicycloC₅₋₁₀alkyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents;

G¹⁰ and G⁴¹ are each independently halo, oxo, —CF₃, —OCF₃, —OR²,—NR²R³(R^(2a))_(j1), —C(O)R², —CO₂R², —CONR²R³, —NO₂, —CN, —S(O)_(j1)R²,—SO₂NR²R³, —NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a),—NR²S(O)_(j1)R³, —C(═S)OR², —C(═O)SR², —NR²C(═NR³)NR^(2a)R^(3a),—NR²C(═NR³)OR^(2a), —NR²C(═NR³)SR^(2a), —OC(═O)OR², —OC(═O)NR²R³,—OC(=O)SR², —SC(═O)OR², —SC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀-alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, oxo, —CF₃, —OCF₃, —OR²²² ,—NR²²²R³³³(R^(222a))_(j1a), —C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —NO₂,—CN, —S(O)_(j1a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²²,—C(═O)SR²²², —NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a), —NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³,—OC(═O)SR²²², —SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents;

or G¹⁰ optionally is —(X¹)_(n)—(Y¹)_(m)—R⁴;

or G⁴¹ optionally is —(X¹)_(n)—(Y¹)_(m)—C₀₋₁₀alkyl;

or G¹⁰ and G⁴¹ are each optionally independently aryl-C₀₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₀₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²², —NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²², —CONR²²²R³³³,—NO₂, —CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³,—NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³,—C(═S)OR²²², —C(═O)SR²²², —NR²²²C(═³³³)NR^(222a)R^(333a),—NR²²²C(═NR³³³)OR^(222a), —NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²²,—OC(═O)NR²²²R³³³, —OC(═O)SR²²², —SC(═O)OR²²², or —SC(═O)NR²²²R³³³substituents;

G¹¹ is halo, oxo, —CF₃, —OCF₃, OR²¹, —NR²¹R³¹(R^(21a))_(j3), —C(O)R²¹,—CO₂R²¹, —CONR²¹R³¹, —NO₂, —CN, —S(O)_(j3)R²¹, —SO₂NR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR²¹R^(21a), —NR²¹S(O)_(j3)R³¹,—C(═S)OR²¹, —C(═O)SR²¹, —NR²¹C(═NR³¹)NR^(21a)R^(31a),—NR²¹C(═NR³¹)OR^(21a), —NR²¹C(═NR³¹)SR^(21a), —OC(═O)OR²¹,—OC(═O)NR²¹R³¹, —OC(═O)SR²¹, —SC(═O)OR²¹, —SC(═O)NR²¹R³¹, —P(O)OR²¹OR³¹,C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(2221a))_(j3a), —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j3a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(2221a),—NR²²²¹S(O)_(j3a)R^(333l), —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), —NR²²²¹C(═NR³³³¹OR^(2221a),—NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents;

or G¹¹ is aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, anyof which is optionally substituted with one or more independent halo,—CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a), —C(O)R²²²¹,—CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹, —SO NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═)NR³³³¹R^(2221a),—NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), —NR²²²¹C(═NR³³³¹)OR^(2221a),—NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —SC(═O)NR²²²¹R³³³¹substituents;

or G¹¹ is C, taken together with the carbon to which it is attachedforms a C═C double bond which is substituted with R⁵ and G¹²;

R², R^(2a), R³, R^(3a), R²²², R^(222a), R³³³, R^(333a), R²¹, R^(21a),R³¹, R^(31a), R²²²¹, R^(2221a), R³³³¹, and R^(3331a) are eachindependently C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, orhetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted by one ormore independent G¹³ substituents;

or in the case of —NR²R³(R^(2a))_(j1) or —NR²¹R³¹(R^(21a))_(j3) or—NR²²²R³³³(R^(222a))_(j1a) or —NR²²²R³³³(R^(222a))_(j2a) or—NR²²²¹R³³³¹(R^(2221a))_(j3a), R² and R³, or R²¹ and R³¹, or R²²² andR³³³, or R²²²¹ and R³³³¹, respectfully, are optionally taken togetherwith the nitrogen atom to which they are attached to form a 3-10membered saturated or unsaturated ring, wherein said ring is optionallysubstituted by one or more independent G¹⁴ substituents and wherein saidring optionally includes one or more independent heteroatoms other thanthe nitrogen to which R² and R³, or R²²² and R³³³, or R²²²¹ and R³³³¹are attached;

X¹ and Y¹ are each independently —O—, —NR⁷—, —S(O)_(j4)—, —CR⁵R⁶—,—N(C(O)OR⁷)—, —N(C(O)R⁷)—, —N(SO₂R⁷)—, —CH₂O—, —CH₂S—, —CH₂N(R⁷)—,—CH(NR⁷)—, —CH₂N(C(O)R⁷)—, —CH₂N(C(O)OR⁷)—, —CH₂N(SO₂R⁷)—, —CH(NHR⁷)—,—CH(NHC(O)R⁷)—, —CH(NHSO₂R⁷)—, —CH(NHC(O)OR⁷)—, —CH(OC(O)R⁷)—,—CH(OC(O)NHR⁷)—, —CH═CH—, —C≡C—, —C(═NOR⁷)—, —C(O)—, —CH(OR⁷)—,—C(O)N(R⁷)—, —N(R⁷)C(O)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂— —OC(O)N(R⁷)—,—N(R⁷)C(O)N(R⁸)—, —NR⁷C(O)O—, —S(O)N(R⁷)—, —S(O)₂N(R⁷)—,—N(C(O)R⁷)S(O)—, —N(C(O)R⁷)S(O)₂—, —N(R⁷)S(O)N(R⁸)—, —N(R⁷)S(O)₂N(R⁸)—,—C(O)N(R⁷)C(O)—, —S(O)N(R⁷)C(O)—, —S(O)₂N(R⁷)C(O)—, —OS(O)N(R⁷)—,—OS(O)₂N(R⁷)—, —N(R⁷)S(O)O—, —N(R⁷)S(O)₂O—, —N(R⁷)S(O)C(O)—,—N(R⁷)S(O)₂C(O)—, —SON(C(O)R⁷)—, —SO₂N(C(O)R⁷)—, —N(R⁷)SON(R⁸)—,—N(R⁷)SO₂N(R⁸)—, —C(O)O—, —N(R⁷)P(OR⁸)O—, —N(R⁷)P(OR⁸)—,—N(R⁷)P(O)(OR⁸)O—, —N(R⁷)P(O)(OR⁸)—, —N(C(O)R⁷)P(OR⁸)O—,—N(C(O)R⁷)P(OR⁸)—, —N(C(O)R⁷)P(O)(OR⁸)O—, —N(C(O)R⁷)P(OR⁸)—,—CH(R⁷)S(O)—, —CH(R⁷)S(O)₂—, —CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—,—CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)O—, —CH(R⁷)S—, —CH(R⁷)N(R⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(SO₂R⁸)—,—CH(R⁷)C(═NOR⁸)—, —CH(R⁷)C(O)—, —CH(R⁷)CH(OR⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, —CH(R⁷)N(R⁸)S(O)₂—,—CH(R⁷)OC(O)N(R⁸)—, —CH(R⁷)N(R⁸)C(O)N(R^(7a))—, —CH(R⁷)NR⁸C(O)O—,—CH(R⁷)S(O)N(R⁸)—, —CH(R⁷)S(O)₂N(R⁸)—, —CH(R⁷)N(C(O)R⁸)S(O)—,—CH(R⁷)N(C(O)R⁸)S(O)—, —CH(R⁷)N(R⁸)S(O)N(R^(7a))—,—CH(R⁷)N(R⁸)S(O)₂N(R^(7a))—, —CH(R⁷)C(O)N(R)C(O)—,—CH(R⁷)S(O)N(R⁸)C(O)—, —CH(R⁷)S(O)₂N(R⁸)C(O)—, —CH(R⁷)OS(O)N(R⁸)—,—CH(R⁷)OS(O)₂N(R⁸)—, —CH(R⁷)N(R⁸)S(O)O—, —CH(R⁷)N(R⁸)S(O)₂O—,—CH(R⁷)N(R⁸)S(O)C(O)—, —CH(R⁷)N(R⁸)S(O)₂C(O)—, —CH(R⁷)SON(C(O)R⁸)—,—CH(R⁷)SO₂N(C(O)R⁸)—, —CH(R⁷)N(R⁸)SON(R^(7a))—,—CH(R⁷)N(R⁸)SO₂N(R^(7a))—, —CH(R⁷)C(O)O—, —CH(R⁷)N(R⁸)P(OR^(7a))O—,—CH(R⁷)N(R⁸)P(OR^(7a))—, —CH(R⁷)N(R⁸)P(O)(OR^(7a))O—,—CH(R⁷)N(R⁸)P(O)(OR^(7a))—, —CH(R⁷)N(C(O)R⁸)P(OR^(7a))O—,—CH(R⁷)N(C(O)R⁸)P(OR^(7a))—, —CH(R⁷)N(C(O)R⁸)P(O)(OR^(7a))O—, or—CH(R⁷)N(C(O)R⁸)P(OR^(7a))—;

or X¹ and Y¹ are each independently represented by one of the followingstructural formulas:

R¹⁰, taken together with the phosphinamnide or phosphonamide, forms a5-, 6-, or 7-membered aryl, heteroaryl, or heterocyclyl ring system;

R⁵, R⁶, G¹², G¹³, G¹⁴, and G¹⁵ are each independently a C₀₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, orhetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR⁷⁷, —NR⁷⁷R⁸⁷, —C(O)R⁷⁷, —CO₂R⁷⁷,CONR⁷⁷R⁸⁷, —NO₂, —CN, —S(O)_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷, —NR⁷⁷C(═O)R⁸⁷,—NR⁷⁷C(═O)OR⁸⁷, —NR⁷⁷C(═O)NR⁸⁷R^(77a), —NR⁷⁷S(O)_(j5a)R⁸⁷, —C═S)OR⁷⁷,—C(═O)SR⁷⁷, —NR⁷⁷C(═NR⁸⁷)NR^(77a)R^(87a), —NR⁷⁷C(═NR⁸⁷)OR^(77a),—NR⁷⁷C(═NR⁸⁷)SR^(77a), —OC(═O)OR⁷⁷, —OC(═O)NR⁷⁷R⁸⁷, —OC(═O)SR⁷⁷,—SC(═O)OR⁷⁷, —P(O)OR⁷⁷OR⁸⁷, or —SC(═O)NR⁷⁷R⁸⁷ substituents;

or R⁵ with R⁶ are optionally taken together with the respective carbonatom to which they are attached form a 3-10 membered saturated orunsaturated ring, wherein said ring is optionally substituted with R⁶⁹and wherein said ring optionally includes one or more independentheteroatoms;

R⁷, R^(7a), and R⁸ are each independently acyl, C₀₋₁₀alkyl,C₂₋₁₀alkenyl, aryl, heteroaryl, heterocyclyl or cycloC₃₋₁₀alkyl, any ofwhich is optionally substituted by one or more independent G¹⁵substituents;

R⁴ is C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl, heteroaryl,cycloC₃₋₁₀alkyl, heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl,any of which is optionally substituted by one or more independent G⁴¹substituents;

R⁶⁹ is halo, —OR⁴¹, —SH, —NR⁴¹R⁵¹, —CO₂R⁴¹, —CONR⁴¹R⁵¹, —NO₂, —CN,—S(O)_(j6)R⁴¹, —SO₂NR⁴¹R⁵¹, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, cyano, nitro, —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸, or—NR⁷⁷⁸R⁸⁸⁸ substituents;

or R⁶⁹ is aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl,mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl,mono(hetaryl)aminoC₁₋₆alkyl, di(hetaryl)aminoC₁₋₆alkyl, or—N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally substitutedwith one or more independent halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,—SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents;

or in the case of —NR⁴¹R⁵¹, R⁴¹ and R⁵¹ are optionally taken togetherwith the nitrogen atom to which they are attached to form a 3-10membered saturated or unsaturated ring, wherein said ring is optionallysubstituted with one or more independent halo, cyano, hydroxy, nitro,C₁₋₁₀alkoxy, —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents and wherein saidring optionally includes one or more independent heteroatoms other thanthe nitrogen to which R⁴¹ and R⁵¹ are attached;

R⁴¹, R⁵¹, R⁷⁷, R^(77a), R⁸⁷, R^(87a), R⁷⁷⁸, and R⁸⁸⁸ are eachindependently C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl,C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,diC₁₋₆alkylaminocarbonyl, mono(aryl)aminocarbonyl,di(aryl)aminocarbonyl, C₁₋₁₀alkyl(aryl)aminocarbonyl,mono(hetaryl)aminocarbonyl, di(hetaryl)aminocarbonyl, or C₁₋₁₀alkylalkyl(hetaryl)aminocarbonyl, any of which is optionally substituted withone or more independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,—SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents;

or R⁴¹, R⁵¹, R⁷⁷, R^(77a), R⁸⁷, R^(87a), R⁷⁷⁸, and R⁸⁸⁸ are eachindependently aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl,mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl,mono(hetaryl)aminoC₁₋₆alkyl, di(hetaryl)aminoC₁₋₆alkyl, or—N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally substitutedwith one or more independent halo, cyano, nitro, —(C₀₋₄alkyl),C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,—CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or—N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; and

n, m, j1, j1a, j2a, j3, j3a, j4, j5a, and j6 are each independently 0,1, or 2.

In an aspect of the present invention, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, heterocyclyl, or heterobicycloC₅₋₁₀alkyl, any of which isoptionally substituted by one or more independent G¹¹ substituents andthe other variables are described as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, orheterocyclyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents and the other variables are described asabove for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents and the other variables are described as above for FormulaI.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, any of which isoptionally substituted by one or more independent G¹⁰ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is heteroaryl¹, which is optionally substitutedby one or more independent G¹⁰ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹, which is optionally substituted byone or more independent G¹⁰ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, any of which isoptionally substituted by one or more independent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionally substituted with one or more independent oxo, —CF₃, —OCF₃,—OR²²², NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²(C═O)NR³³³R^(222a),—NR²²²S(O)_(j1a)R³³³, —NR²²²C(═NR³³³)NR^(222a)R^(333a), or—O(C═O)NR²²²R³³³ substituents; or G¹⁰ is —(X¹)_(n)—(Y¹)_(m)—R⁴; or G¹⁰is aryl-C₀₋₁₀alkyl or hetaryl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j2a)R³³³, —NR²²²C(═NR³³³)NR^(222a)R^(333a), or—OC(═O)NR²²²R³³³ substituents; and the other variables are described asabove for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, any of which isoptionally substituted by one or more independent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR², —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independent oxo,—CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³,—SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —OC(═O)NR²²²R³³³ substituents; orG¹⁰ is —(X¹)_(n)—(Y¹)_(m)—R⁴; and the other variables are described asabove for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; and theother variables are described as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O—, —NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or—C(O)—; wherein n and m are both 1; j4 is 1 or 2; and the othervariables are described as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CR⁵R⁶—; wherein n and m are both1; and the other variables are described as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CH₂—; wherein n and m are both 1;and the other variables are described as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein R⁴is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl,cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which is optionallysubstituted by one or more independent G⁴¹ substituents; and the othervariables are described as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O—, —NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or—C(O)—; wherein n and m are both 1; j4 is 1 or 2; wherein R⁴ isC₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl,cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which is optionallysubstituted by one or more independent G⁴¹ substituents; and the othervariables are described as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CR⁵R⁶—; wherein n and m are both1; wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl,heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CH₂—; wherein n and m are both 1;wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl,heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein R⁴is aryl or heteroaryl, any of which is optionally substituted by one ormore independent G⁴¹ substituents; and the other variables are describedas above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O—, —NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or—C(O)—; wherein n and m are both 1; j4 is 1 or 2; wherein R⁴ is aryl orheteroaryl, any of which is optionally substituted by one or moreindependent G⁴¹ substituents; and the other variables are described asabove for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CR⁵R⁶—; wherein n and m are both1; wherein R⁴ is aryl or heteroaryl, any of which is optionallysubstituted by one or more independent G⁴¹ substituents; and the othervariables are described as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CH₂—; wherein n and m are both 1;wherein R⁴ is aryl or heteroaryl, any of which is optionally substitutedby one or more independent G⁴¹ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ substituted by said one to fiveindependent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; n and m are both 1; R⁴ is aryloptionally substituted by one or more G⁴¹ substituents; X¹ is —O—; Y¹ is—CH₂—; and the other variables are described as above for Formula I.

In an embodiment of this aspect, a compound is represented by Formula I,or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein R⁴is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl,cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which is optionallysubstituted by one or more independent G⁴¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a),—C(O)R^(222a), —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In a second aspect of the present invention, a compound is representedby Formula I, or a pharmaceutically acceptable salt thereof, wherein R¹is aryl, heteroaryl, aralkyl, or heteroaralkyl, any of which isoptionally substituted by one or more independent G¹¹ substituents andthe other variables are described as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl or heteroaryl, any of which is optionally substituted by one ormore independent G¹¹ substituents and the other variables are describedas above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹ substituentsand the other variables are described as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, any of which isoptionally substituted by one or more independent G¹⁰ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is heteroaryl¹, which is optionally substitutedby one or more independent G¹⁰ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹, which is optionally substituted byone or more independent G¹⁰ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is heteroaryl¹, which is optionally substitutedby one or more independent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R²a, —NR²S(O)_(j1)R³, —OC(═O)OR²,—OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀-alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionally substituted with one or more independent oxo, —CF₃, —OCF₃,—OR²²², —NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²(C═O)NR³³³R^(222a),—NR²²²S(O)_(j1a)R³³³, —NR²²²C(═NR³³³)NR^(222a)R^(333a), or—OC(═O)NR²²²R³³³ substituents; or G¹⁰ is —(X¹)_(n)—(Y¹)_(m)—R⁴; or G¹⁰is aryl-C₀₋₁₀alkyl or hetaryl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j2a)R³³³, —NR²²²C(═NR³³³)NR^(222a)R^(333a), or—OC(═O)NR²²²R³³³ substituents; and the other variables are described asabove for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹, which is optionally substituted byone or more independent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR₂, —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independent oxo,—CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³,—SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²(C═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —OC(═O)NR²²²R³³³ substituents; orG¹⁰ is —(X¹)_(n)—(Y¹)_(m)—R⁴; or G¹⁰ is aryl-C₀₋₁₀alkyl orhetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²²,—CO₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³,—NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —OC(═O)NR²²²R³³³ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is heteroaryl¹, which is optionally substitutedby one or more independent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR², —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independent oxo,—CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³,—SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R³³³a, or —OC(═O)NR²²²R³³³ substituents; or G¹⁰is —(X¹)_(n)—(Y¹)_(m)—R⁴; and the other variables are described as abovefor Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹, which is optionally substituted byone or more independent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR², —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independent oxo,—CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³,—SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —OC(═O)NR²²²R³³³ substituents; orG¹⁰ is —(X¹)_(n)—(Y¹)_(m)—R⁴; and the other variables are described asabove for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹; wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein nand m are both 1; and the other variables are described as above forFormula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O—, —NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or—C(O)—; wherein n and m are both 1; j4 is 1 or 2; and the othervariables are described as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CR⁵R⁶—; wherein n and m are both1; and the other variables are described as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CH₂—; wherein n and m are both 1;and the other variables are described as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹; wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein nand m are both 1; wherein R⁴is C₀₋₁₀alkyl, aryl, heteroaryl,cycloC₃₋₁₀alkyl, heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl,any of which is optionally substituted by one or more independent G⁴¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O—, —NR⁷—, CR⁵R⁶—, —S(O)_(j4)—, or—C(O)—; wherein n and m are both 1; j4 is 1 or 2; wherein R⁴ isC₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl,cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which is optionallysubstituted by one or more independent G⁴¹ substituents; and the othervariables are described as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or CR⁵R⁶—; wherein n and m are both 1;wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl,heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or CH₂—; wherein n and m are both 1;wherein R⁴is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl,heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹; wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein nand m are both 1; R⁴is aryl or heteroaryl, any of which is optionallysubstituted by one or more independent G⁴¹ substituents; and the othervariables are described as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O—, —NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or—C(O)—; wherein n and m are both 1; j4 is 1 or 2; R⁴ is aryl orheteroaryl, any of which is optionally substituted by one or moreindependent G⁴¹ substituents; and the other variables are described asabove for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CR⁵R⁶—; wherein n and m are both1; R⁴ is aryl or heteroaryl, any of which is optionally substituted byone or more independent G⁴¹ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CH₂—; wherein n and m are both 1;wherein R⁴ is aryl or heteroaryl, any of which is optionally substitutedby one or more independent G⁴¹ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹; wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein nand m are both 1; wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl,cycloC₃₋₁₀alkyl, heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl,any of which is optionally substituted by one or more independent G⁴¹substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R²²²¹a)_(j3a), —C(O)R²²²¹,—CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(2221a),—NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), —NR²²²¹C(═NR³³³¹)OR^(2221a),—NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O—, —NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or—C(O)—; wherein n and m are both 1; j4 is 1 or 2; wherein R⁴ isC₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl,cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which is optionallysubstituted by one or more independent G⁴¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR^(2221c)(═NR³³³¹)SR^(2221a),—OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or—SC(═O)NR²²²¹R³³³¹ substituents; and the other variables are describedas above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CR⁵R⁶—; wherein n and m are both1; wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl,heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹OC(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CH₂—; wherein n and m are both 1;wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl,heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isphenyl optionally substituted by one or more independent G¹¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl, optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ substituted by said one to fiveindependent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; n and m are both 1; R⁴ is aryloptionally substituted by one or more G⁴¹ substituents; X¹ is —O—; Y¹ is—CH₂—; and the other variables are described as above for Formula I.

In an embodiment of this second aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isphenyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ substituted by said one to fiveindependent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; n and m are both 1; R⁴ is aryloptionally substituted by one or more G⁴¹ substituents; X¹ is —O—; Y¹ is—CH₂—; and the other variables are described as above for Formula I.

In a third aspect of the present invention, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl or heterocyclyl, any of which is optionally substitutedby one or more independent G¹¹ substituents and the other variables aredescribed as above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents and the other variables are described as above for FormulaI.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, any of which isoptionally substituted by one or more independent G¹⁰ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more hindependent G¹¹substituents; wherein Q¹ is heteroaryl¹, which is optionally substitutedby one or more independent G¹⁰ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹, which is optionally substituted byone or more independent G¹⁰ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is heteroaryl¹, which is optionally substitutedby one or more independent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR², —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₀₋₁₀alkylthioC₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀oalkyl, orheterocyclyl-C₂₋₁₀alkenyl, any of which is optionally substituted withone or more independent oxo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²²,—CO₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³,—NR²²²C(═O)OR³³³, —N²²²(C═O)NR³³³R^(222a), —N²²²S(O)_(j1a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a) or —O(C═O)NR²²²R³³³ substituents; orG¹⁰ is —(X¹)_(n)—(Y¹)_(m)—R⁴; or G¹⁰ is aryl-C₀₋₁₀alkyl orhetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, OR²²², —NR²²²R³³³, —C(O)R²²²,—CO₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³,—NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a), R³³³—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —OC(═O)NR²²²R³³³ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹, which is optionally substituted byone or more independent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR², —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independent oxo,—CF₃, —OCF₃, —OR²²², NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²² R³³³,—SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²(C═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —O(C═O)NR²²²R³³³ substituents; orG¹¹ is —(X¹)_(n)—(Y¹)_(m)—R⁴; or G¹⁰ is aryl-C₀₋₁₀alkyl orhetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —R²²², —NR²²²R³³³, —C(O)R²²²,—CO₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³,—NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³,—NR²²²C(═NR³³³)NR²²²²R^(333a), or —OC(═O)NR²²²R³³³ substituents; and theother variables are described as above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is heteroaryl¹, which is optionally substitutedby one or more independent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR², —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independent oxo,—CF₃, —OCF₃, OR²²², —NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³,—SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—N²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³,—N²²²C(═NR³³³)NR^(222a)R^(333a), or —OC(═O)NR²²²R³³³ substituents; orG¹⁰ is —(X¹)_(n)—(Y¹)_(m)—R⁴; and the other variables are described asabove for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹, which is optionally substituted byone or more independent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR², —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independent oxo,—CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³,—SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R³³³a, or —OC(═O)NR²²²R³³³ substituents; or G¹⁰is —(X¹)_(n)—(Y¹)_(m)—R⁴; and the other variables are described as abovefor Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; and theother variables are described as above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O—, —NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or—C(O)—; wherein n and m are both 1; j4 is 1 or 2; and the othervariables are described as above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or CR⁵R⁶—, —S(O)_(j4)—, or —C(O)—;wherein n and m are both 1; and the other variables are described asabove for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴, and whereinX¹ and Y¹ are each independently —O— or —CH₂—, —S(O)_(j4)—, or —C(O)—;and wherein n and m are both 1; and the other variables are described asabove for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein R⁴is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl,cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which is optionallysubstituted by one or more independent G⁴¹ substituents; and the othervariables are described as above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O—, —NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or—C(O)—; wherein n and m are both 1; j4 is 1 or 2; wherein R⁴ isC₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl,cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which is optionallysubstituted by one or more independent G⁴¹ substituents; and the othervariables are described as above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CR⁵R⁶—, —S(O)_(j4)—, or —C(O)—;wherein n and m are both 1; wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl,cycloC₃₋₁₀alkyl, heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl,any of which is optionally substituted by one or more independent G⁴¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴, and whereinX¹ and Y¹ are each independently —O— or —CH₂—, —S(O)_(j4)—, or —C(O)—;and wherein n and m are both 1; wherein R⁴ is C₋₁₀alkyl, aryl,heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl, cycloC₃₋₁₀alkenyl, orheterocycloalkenyl, any of which is optionally substituted by one ormore independent G⁴¹ substituents; and the other variables are describedas above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein R⁴is aryl or heteroaryl, any of which is optionally substituted by one ormore independent G⁴¹ substituents; and the other variables are describedas above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O—, —NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or—C(O)—; wherein n and m are both 1; j4 is 1 or 2; wherein R⁴ is aryl orheteroaryl, any of which is optionally substituted by one or moreindependent G⁴¹ substituents; and the other variables are described asabove for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CR⁵R⁶—, —S(O)_(j4)—, or —C(O)—;wherein n and m are both 1; wherein R⁴ is aryl or heteroaryl, any ofwhich is optionally substituted by one or more independent G⁴¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CH₂—, —S(O)_(j4)—, or —C(O)—;wherein n and m are both 1; wherein R⁴ is aryl or heteroaryl, any ofwhich is optionally substituted by one or more independent G⁴¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ substituted by said one to fiveindependent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; n and m are both 1; R⁴ is aryloptionally substituted by one or more G⁴¹ substituents; X¹ is —O—; andY¹ is —CH₂—; and the other variables are described as above for FormulaI.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹; wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein R⁴is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl,cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which is optionallysubstituted by one or more independent G⁴¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O—, —NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or—C(O)—; wherein n and m are both 1; j4 is 1 or 2; wherein R⁴ isC₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl,cycloC₃₋₁₀alkenyl , or heterocycloalkenyl, any of which is optionallysubstituted by one or more independent G⁴¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹, 13SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CR⁵R⁶—, —S(O)_(j4)—, or —C(O)—;wherein n and m are both 1; wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl,cycloC₃₋₁₀alkyl, heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl,any of which is optionally substituted by one or more independent G⁴¹substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isheterocyclyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, wherein Q¹ issubstituted by said one to five independent G¹⁰ substituents wherein atleast one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹and Y¹ are each independently —O— or —CH₂—, —S(O)_(j4)—, or —C(O)—;wherein n and m are both 1; wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl,cycloC₃₋₁₀alkyl, heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl,any of which is optionally substituted by one or more independent G⁴¹substituents;

wherein G¹¹ is CR²¹, —NR²¹R³¹, —CO₂R²¹, —(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which optionally substituted with one or more independent halo,oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a), —C(O)R²²²¹,—CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(2221a),—NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), —NR²²²¹C(═NR³³³¹)OR^(2221a),—NR²²²¹C(═NR³³³¹)SR^(222a), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isrepresented by the structural formula:

wherein Z² is a heterocyclyl containing a N substituted by G¹¹ and theother variables are described as above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isrepresented by the structural formula:

wherein G¹¹ is —C(O)R²¹, —CO₂R²¹, —CONR²¹R³¹, —SO₂NR²¹R³¹,—S(O)_(j3)R³¹, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, orheterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionally substituted with one or more independent oxo, —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹, —OC(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or —OC(═O)NR²²²¹R³³³¹substituents;

or G¹¹ is aryl-C₀₋₁₀alkyl or hetaryl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or —OC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ isrepresented by the structural formula:

wherein G¹¹ is —C(O)R²¹, —CO₂R²¹, —CONR²¹R³¹, —SO₂NR²¹R³¹,—S(O)_(j3)R³¹, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, orheterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionally substituted with one or more independent oxo, —CF₃, —OCF₃,—OR²²²¹, —N²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or —OC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this third aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, above whereinR¹ is represented by the structural formula:

wherein G¹¹ is —C(O)R²¹, —CO₂R²¹, —CONR²¹R³¹, —SO₂NR²¹R³¹,—S(O)_(j3)R³¹, C₀₋₁₀alkyl, C₂₋₁₋alkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, orheterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionally substituted with one or more independent oxo, —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR²²²¹R³³³¹, —NR²²²¹S(O)_(j3a)R³³³¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or —OC(═O)NR²²²¹R³³³¹substituents;

or aryl-C₀₋₁₀alkyl or hetaryl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —CF₃, —OR²²²¹,—NR²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR²²²¹R³³³¹,—NR²²²¹S(O)_(j3a)R³³³¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or—OC(═O)NR²²²¹R³³³¹ substituents; and the other variables are describedas above for Formula I.

In an embodiment of this third aspect, a compound is represented byFormula I, or a phannaceutically acceptable salt thereof, wherein R¹ isrepresented by the structural formula:

wherein G¹¹ is —C(O)R²¹, —CO₂R²¹, —CONR²¹R³¹, —SO₂NR²¹R³¹,—S(O)_(j3)R³¹, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, orheterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionally substituted with one or more independent oxo, —CF₃, —OCF₃,—O²²²¹, —NR²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR²²²¹R³³³¹, —NR²²²¹S(O)_(j3a)R³³³¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or —OC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In a fourth aspect of the present invention, a compound is representedby Formula I, or a pharmaceutically acceptable salt thereof, wherein R¹is cycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents and the other variables are described as above for FormulaI.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ or heteroaryl¹, any of which isoptionally substituted by one or more independent G¹⁰ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is heteroaryl¹, which is optionally substitutedby one or more independent G¹⁰ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹, which is optionally substituted byone or more independent G¹⁰ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is heteroaryl¹, which is optionally substitutedby one or more independent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR², —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclylo-C₀₋₁₀alkyl, orheterocyclyl-C₂₋₁₀alkenyl, any of which is optionally substituted withone or more independent oxo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²²,—CO₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³,—NR²²²C(═O)OR³³³, —NR²²²(C═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —O(C═O)NR²²²R³³³ substituents; orG¹¹ is —(X¹)_(n)—(Y¹)_(m)—R⁴; or G¹⁰ is aryl-C₀₋₁₀alkyl orhetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²²,—CO₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³, —NR²²² C(═O)R³³³,—NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —OC(═O)NR²²²R³³³ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ optionally substituted by one or moreindependent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —ONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionally substituted with one or more independent oxo, —CF₃, —OCF₃,—OR²²², —NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²(C═O)NR³³³R^(222a),—NR²²²S(O)_(j1a)R³³³, —NR²²²C(═NR³³³)NR^(222a)R^(333a), or—O(C═O)NR²²²R³³³ substituents; or G¹⁰ is —(X¹)_(n)—(Y¹)—R⁴; or G¹⁰ isaryl-C₀₋₁₀alkyl or hetaryl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³,—NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a),—NR²²²S(O)_(j2a)R³³³, —NR²²²C(═NR³³³)NR^(222a)R^(333a), or—OC(═O)NR²²²R³³³ substituents; and the other variables are described asabove for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹, which is optionally substituted byone or more independent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR², —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more indepndent oxo,—CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³,—SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—N²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a) or —OC(═O)NR²²²R³³³ substituents; orG¹¹ is —(X¹)_(n)—(Y¹)_(m)—R⁴; and the other variables are described asabove for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is substituted by said one to five independentG¹⁰ substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; and the other variables are described as abovefor Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is substituted by said one to five independentG¹⁰ substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are each independently —O—,—NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or —C(O)—; and the other variables aredescribed as above for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is substituted by said one to five independentG¹⁰ substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are each independently —O— or—CR⁵R⁶—; and the other variables are described as above for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is substituted by said one to five independentG¹⁰ substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴, and wherein X¹ and Y¹ are each independently —O—or —CH₂—; and the other variables are described as above for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is substituted by said one to five independentG¹⁰ substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl,cycloC₃₋₁₀alkyl, heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl,any of which is optionally substituted by one or more independent G⁴¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is substituted by said one to five independentG¹⁰ substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are each independently —O—,—NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or —C(O)—; wherein R⁴ is C₀₋₁₀alkyl, aryl,heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl, cycloC₃₋₁₀alkenyl, orheterocycloalkenyl, any of which is optionally substituted by one ormore independent G⁴¹ substituents; and the other variables are describedas above for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is substituted by said one to five independentG¹⁰ substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are each independently —O— or—CR⁵R⁶—; wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl,heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is substituted by said one to five independentG¹⁰ substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are each independently —O— or—CH₂—; wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl,heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is substituted by said one to five independentG¹⁰ substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are each independently —O—,—NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or —C(O)—; wherein R⁴ is aryl orheteroaryl, any of which is optionally substituted by one or moreindependent G⁴¹ substituents; and the other variables are described asabove for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is aryl¹ substituted by said one to fiveindependent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein n and m are both 1;wherein R⁴ is aryl optionally substituted by one or more G⁴¹substituents; X¹ is —O—; Y¹ is —CH₂—; and the other variables aredescribed as above for Formula I.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is substituted by said one to five independentG¹⁰ substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl,cycloC₃₋₁₀alkyl, heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl,any of which is optionally substituted by one or more independent G⁴¹substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, NR²²²¹R³³³¹(R^(2221a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is substituted by said one to five independentG¹⁰ substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are each independently —O—,—NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or —C(O)—; wherein R⁴ is C₀₋₁₀alkyl, aryl,heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl, cycloC₃₋₁₀alkenyl, orheterocycloalkenyl, any of which is optionally substituted by one ormore independent G⁴¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, NR²²²¹R³³³¹(R^(2221a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is substituted by said one to five independentG¹⁰ substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are each independently —O— or—CR⁵R⁶—; wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl,heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(222a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC (═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this fourth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscycloC₃₋₁₀alkyl optionally substituted by one or more independent G¹¹substituents; wherein Q¹ is substituted by said one to five independentG¹⁰ substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are each independently —O— or—CH₂—; wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl,heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In a fifth aspect of the present invention, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; and theother variables are described as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; any ofwhich is optionally substituted by one or more independent G¹⁰substituents; and the other variables are described as above for FormulaI.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is heteroaryl¹, which is optionally substituted by one or moreindependent G¹⁰ substituents; and the other variables are described asabove for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹, which is optionally substituted by one or more independentG¹⁰ substituents; and the other variables are described as above forFormula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is heteroaryl¹, which is optionally substituted by one or moreindependent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR², —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC,-Ioalkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independent oxo,—CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³,—SO₂NR²²²R³³³, —NR²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²(C═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —O(C═O)NR²²²R³³³ substituents; orG¹¹ is —(X¹)_(n)—(Y¹)_(m)—R⁴; or G¹⁰ is aryl-C₀₋₁₀alkyl orhetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²²,—O₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —OC(═O)NR²²²R³³³ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹, which is optionally substituted by one or more independentG¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR², —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independent oxo,—CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³,—SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²(C═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —O(C═O)NR²²²R³³³ substituents; orG¹¹ is —(X¹)_(n)—(Y¹)_(m)—R⁴; or G¹⁰ is aryl-C₀₋₁₀alkyl orhetaryl-C₀₋₁₀alkyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²²,—CO₂R²²², —CONR²²²R³³³, —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³,—NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —OC(═O)NR²²²R³³³ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is heteroaryl¹, which is optionally substituted by one or moreindependent G¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR², —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈allkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independent oxo,—CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²²R³³³,—SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —OC(═O)NR²²²R³³³ substituents; orG¹⁰ is —(X¹)_(n)—(Y¹)_(m)—R4; and the other variables are described asabove for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹, which is optionally substituted by one or more independentG¹⁰ substituents;

wherein G¹⁰ is halo, —OR², —NR²R³, —C(O)R², —CO₂R², —CONR²R³, —SO₂NR²R³,—NR²C(═O)R³, —NR²C(═O)OR³, —NR²C(═O)NR³R^(2a), —NR²S(O)_(j1)R³,—OC(═O)OR², —OC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independent oxo,—CF₃, —OCF₃, —OR²²², —NR²²²R³³³, —C(O)R²²², —CO₂R²²², —CONR²²² ^(R) ³³³,—SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³,—NR²²²C(═NR³³³)NR^(222a)R^(333a), or —OC(═O)NR²²²R³³³ substituents; orG¹¹ is —(X¹)_(n)—(Y¹)_(m)—R⁴; and the other variables are described asabove for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ or heteroaryl¹, wherein Q¹ is substituted by said one tofive independent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein n and m are both 1; andthe other variables are described as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormnula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ or heteroaryl¹, wherein Q¹ is substituted by said one tofive independent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are eachindependently —O—, —NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or —C(O)—; wherein n andm are both 1; j4 is 1 or 2; and the other variables are described asabove for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ or heteroaryl¹, wherein Q¹ is substituted by said one tofive independent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are eachindependently —O— or —CR⁵R⁶—; wherein n and m are both 1; and the othervariables are described as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ or heteroaryl¹, wherein Q¹ is substituted by said one tofive independent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are eachindependently —O— or —CH₂—; wherein n and m are both 1; and the othervariables are described as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ or heteroaryl¹, wherein Q¹ is substituted by said one tofive independent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein n and m are both 1;wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl,heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ or heteroaryl¹, wherein Q¹ is substituted by said one tofive independent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are eachindependently —O—, —NR—, —CR⁵R⁶—, —S(O)_(j4)—, or —C(O)—; wherein n andm are both 1; j4 is 1 or 2; wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl,cycloC₃₋₁₀alkyl, heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl,any of which is optionally substituted by one or more independent G⁴¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ or heteroaryl¹, wherein Q¹ is substituted by said one tofive independent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are eachindependently —O— or —CR⁵R⁶—; wherein n and m are both 1; wherein R⁴isC₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl,cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which is optionallysubstituted by one or more independent G⁴¹ substituents; and the othervariables are described as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ or heteroaryl¹, wherein Q¹ is substituted by said one tofive independent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are eachindependently —O— or —CH₂—; wherein n and m are both 1; wherein R⁴ isC₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl, heterocyclyl,cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which is optionallysubstituted by one or more independent G⁴¹ substituents; and the othervariables are described as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ or heteroaryl¹, wherein Q¹ is substituted by said one tofive independent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein n and m are both 1;wherein R⁴ is aryl or heteroaryl, any of which is optionally substitutedby one or more independent G⁴¹ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ or heteroaryl¹, wherein Q¹ is substituted by said one tofive independent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are eachindependently —O—, —NR⁷—, —CR⁵R⁶—, —S(O)_(j4)—, or —C(O)—; wherein n andm are both 1; j4 is 1 or 2; wherein R⁴ is aryl or heteroaryl, any ofwhich is optionally substituted by one or more independent G⁴¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ or heteroaryl¹, wherein Q¹ is substituted by said one tofive independent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(m)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are eachindependently —O— or —CR⁵R⁶—; wherein n and m are both 1; wherein R⁴isaryl or heteroaryl, any of which is optionally substituted by one ormore independent G⁴¹ substituents; and the other variables are describedas above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ or heteroaryl¹, wherein Q¹ is substituted by said one tofive independent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ and Y¹ are eachindependently —O— or —CH₂—; wherein n and m are both 1; wherein R⁴ isaryl or heteroaryl, any of which is optionally substituted by one ormore independent G⁴¹ substituents; and the other variables are describedas above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n and m are both 1; R⁴ is aryl optionally substituted by one or more G⁴¹substituents; X¹ is —O—; Y¹ is —CH₂—; and the other variables aredescribed as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl which is substituted at the 3-position by G¹¹;wherein Q¹ is aryl¹ substituted by said one to five independent G¹⁰substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; n and m are both 1; R⁴ is aryl optionallysubstituted by one or more G⁴¹ substituents; X¹ is —O—; and Y¹ is —CH₂—;and the other variables are described as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is aryl¹ or heteroaryl¹, wherein Q¹ is substituted by said one tofive independent G¹⁰ substituents wherein at least one of said G¹⁰substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein n and m are both 1;wherein R⁴ is C₀₋₁₀alkyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl,heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a))_(j3a),—(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;wherein X¹ and Y¹ are each independently —O—, —NR⁷—, —CR⁵R⁶—,—S(O)_(j4)—, or —C(O)—; wherein n and m are both 1; j4 is 1 or 2; andthe other variables are described as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;wherein X¹ and Y¹ are each independently —O— or —CR⁵R⁶—; wherein n and mare both 1; and the other variables are described as above for FormulaI.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;wherein X¹ and Y¹ are each independently —O—, —NR⁷—, —CR⁵R⁶—,—S(O)_(j4)—, or —C(O)—;

wherein G¹¹ is —OR²¹, NR²¹R³¹(R^(21a))₃, —C(O)R²¹, —CO₂R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR²¹R³¹, —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —CF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(333a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR²²²¹R³³³¹, —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(3331a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents;

or G¹¹ is aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, anyof which is optionally substituted with one or more independent halo,—CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a), —C(O)R²²²¹,—CO₂R²²²¹R³³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(2221a),—NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)N^(2221a)R^(3331a), —NR²²²¹C(═NR³³³¹)OR^(2221a),—NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this fifth aspect, a compound is represented byFormula I, or a pharrnaceutically acceptable salt thereof, wherein R¹ iscis- or trans-cyclobutyl substituted at the 3-position by G¹¹ or R¹ iscis- or trans-cyclohexyl substituted at the 4-position by G¹¹; whereinQ¹ is substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;wherein X¹ and Y¹ are each independently —O— or —CR⁵R⁶—; and wherein nand m are both 1; j4 is 1 or 2;

wherein G¹¹ is —OR²¹, —NR²¹R³¹(R^(21a))_(j3), —C(O)R²¹, —CO₂R²¹,—CONR²¹R³¹, —NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR²¹R³¹,NR²¹S(O)_(j3)R³¹, —OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl,cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, orheterocyclyl-C₂₋₁₀alkenyl, any of which is optionally substitutedwith-one or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(333a))_(j3a), —C(O)R²²²¹, —CO₂R²²²¹, CONR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j3a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR²²²¹R³³³¹, —NR²²²¹S(O)_(j3a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —N²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—N²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(3331a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NRR²²²R³³³¹substituents;

or G¹¹ is aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, anyof which is optionally substituted with one or more independent halo,—CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a), —C(O)R²²²¹,—CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(2221a),—NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), —NR²²²¹C(═NR³³³¹)OR^(2221a),—NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹ substituents; andthe other variables are described as above for Formula I.

In a sixth aspect of the present invention, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—) or 4-(—O—); m is 1; Y¹ is (—CH₂—); R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this sixth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—) or 4-(—O—); m is 1; Y¹ is (—CH₂—); and R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is aryl, heteroaryl, cycloC₃₋₁₀alkyl or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this sixth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3 —(—O—) or 4 —(—O—); m is 1; Y¹ is (—CH₂—); R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is cycloC₃₋₁₀alkyl or heterocyclyl, any of which isoptionally substituted by one or more independent G¹¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this sixth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3 —(—O—) or 4 —(—O—); m is 1; Y¹ is (—CH₂—); R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is cycloC₃₋₁₀alkyl, optionally substituted by one or moreindependent G¹¹ substituents; and the other variables are described asabove for Formula I.

In an embodiment of this sixth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3 —(—O—) or 4(—O—); m is 1; Y¹ is (—CH₂—); and R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is cyclobutyl, cyclopentyl, or cyclohexyl, any of which isoptionally substituted by one or more independent G¹¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this sixth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3 —(—O—) or 4-(—O—); m is 1; Y¹ is (—CH₂—); and R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is cycloC₃₋₁₀alkyl, optionally substituted by one or moreindependent G¹¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R²²²¹)_(j3a), —C(O)R²²²¹,—CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, S(O)_(j3a)R²²²¹, —SO₂NR²²²¹R³³³¹,NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(2221a),—NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), —NR²²²¹C(═NR³³³¹)OR^(2221a),—NR²²²¹C(NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this sixth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3 —(—O—) or 4 —(—O—); m is 1; Y¹ is (—CH₂—); R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is cyclobutyl, cyclopentyl, or cyclohexyl, any of which isoptionally substituted by one or more independent G¹¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═C)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In a seventh aspect of the present invention, a compound is representedby Formula I, or a pharmaceutically acceptable salt thereof, wherein Q¹is phenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is C₀₋₈alkyl or cycloC₃₋₁₀alkyl, anyof which is optionally substituted by one or more independent G⁴¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this seventh aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3 —(—O—); m is 0; R⁴ is C₀₋₈alkyl or cycloC₃₋₁₀alkyl, anyof which is optionally substituted by one or more independent G⁴¹substituents; wherein R¹ is aryl, heteroaryl, cycloC₃₋₁₀alkyl, orheterocyclyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents; and the other variables are described asabove for Formula I.

In an embodiment of this seventh aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3 —(—O—); m is 0; R⁴ is C₀₋₈alkyl or cycloC₃₋₁₀alkyl, anyof which is optionally substituted by one or more independent G⁴¹substituents; wherein R¹ is cycloC₃₋₁₀alkyl or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this seventh aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3 —(—O—); m is 0; R⁴ is C₀₋₈alkyl or cycloC₃₋₁₀alkyl, anyof which is optionally substituted by one or more independent G⁴¹substituents; wherein R¹ is cycloC₃₋₁₀alkyl, optionally substituted byone or more independent G¹¹ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this seventh aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3 —(—O—); m is 0; R⁴ is C₀₋₈alkyl or cycloC₃₋₁₀alkyl, anyof which is optionally substituted by one or more independent G⁴¹substituents; wherein R¹ is cyclobutyl, cyclopentyl, or cyclohexyl, anyof which is optionally substituted by one or more independent G¹¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this seventh aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3 —(—O—); m is 0; R⁴ is C₀₋₈alkyl or cycloC₃₋₁₀alkyl, anyof which is optionally substituted by one or more independent G⁴¹substituents; wherein R¹ is cycloC₃₋₁₀alkyl, optionally substituted byone or more independent G¹¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j4)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j4a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR₂₂₂₁C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j4a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR²²²¹, —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this seventh aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3 —(—O—); m is 0; R⁴ is C₀₋₈alkyl or cycloC₃₋₁₀alkyl, anyof which is optionally substituted by one or more independent G⁴¹substituents; wherein R¹ is cyclobutyl, cyclopentyl, or cyclohexyl, anyof which is optionally substituted by one or more independent G¹¹substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j4)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j4a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j4a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an eighth aspect of the present invention, a compound is representedby Formula I, or a pharmaceutically acceptable salt thereof, wherein Q¹is phenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is C₀₋₆alkyl; and the other variablesare described as above for Formula I.

In an embodiment of this eighth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is C₀₋₆alkyl; wherein R¹ is aryl,heteroaryl, cycloC₃₋₁₀alkyl, or heterocyclyl, any of which is optionallysubstituted by one or more independent G¹¹ substituents; and the othervariables are described as above for Formula I.

In an embodiment of this eighth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is C₀₋₆alkyl; wherein R¹ iscycloC₃₋₁₀alkyl or heterocyclyl, any of which is optionally substitutedby one or more independent G¹¹ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this eighth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is C⁰⁻⁶alkyl; wherein R¹ iscycloC₃₋₁₀alkyl, optionally substituted by one or more independent G¹¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this eighth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is C₀₋₆alkyl; wherein R¹ iscyclobutyl, cyclopentyl, or cyclohexyl, any of which is optionallysubstituted by one or more independent G¹¹ substituents; and the othervariables are described as above for Formula I.

In an embodiment of this eighth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is C₀₋₆alkyl; wherein R¹ iscycloC₃₋₁₀alkyl, optionally substituted by one or more independent G¹¹substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j4)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j4a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j4a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this eighth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is C₀₋₆alkyl; wherein R¹ iscyclobutyl, cyclopentyl, or cyclohexyl, any of which is optionallysubstituted by one or more independent G¹¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j4)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j4a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, R^(2221a),—NR²²²¹S(O)_(j4a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), —NR²²²¹C(═NR³³³¹)OR^(2221a),—NR²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹ substituents; andthe other variables are described as above for Formula I.

In a ninth aspect of the present invention, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; wherein R⁴ is H or methyl; and the othervariables are described as above for Formula I.

In an embodiment of this ninth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; wherein R⁴ is H or methyl; wherein R¹ isaryl, heteroaryl, cycloC₃₋₁₀alkyl, or heterocyclyl, any of which isoptionally substituted by one or more independent G¹¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this ninth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; wherein R⁴ is H or methyl; wherein R¹ iscycloC₃₋₁₀alkyl or heterocyclyl, any of which is optionally substitutedby one or more independent G¹¹ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this ninth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; wherein R⁴ is H or methyl; wherein R¹ iscycloC₃₋₁₀alkyl, optionally substituted by one or more independent G¹¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this ninth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; wherein R⁴ is H or methyl; wherein R¹ iscyclobutyl, cyclopentyl, or cyclohexyl, any of which is optionallysubstituted by one or more independent G¹¹ substituents; and the othervariables are described as above for Formula I.

In an embodiment of this ninth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; wherein R⁴ is H or methyl; wherein R¹ iscycloC₃₋₁₀alkyl, optionally substituted by one or more independent G¹¹substituents;

wherein G¹¹ is —OR², —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j4)R³¹,—OC(═O)OR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,heterocyclyl-C₀₋₁₀-oalkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionally substituted with one or more independent halo, oxo, —CF₃,—OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹,—CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —N²²²¹C(═O)NR³³³¹R^(2221a),—NR²²²¹S(O)_(j4a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)R^(2221a)R^(3331a), —NR²²²¹C(═NR³³³¹)OR^(2221a),—NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this ninth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; wherein R⁴ is H or methyl; wherein R¹ iscyclobutyl, cyclopentyl, or cyclohexyl, any of which is optionallysubstituted by one or more independent G¹¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j4)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j4a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j4a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an tenth aspect of the present invention, a compound is representedby Formula I, or a pharmaceutically acceptable salt thereof, wherein Q¹is phenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is aryl optionally substituted by oneor more independent G⁴¹ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this tenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is aryl optionally substituted by oneor more independent G⁴¹ substituents; wherein R¹ is aryl, heteroaryl,cycloC₃₋₁₀alkyl, or heterocyclyl, any of which is optionally substitutedby one or more independent G¹¹ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this tenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is aryl optionally substituted by oneor more independent G⁴¹ substituents; wherein R¹ is cycloC₃₋₁₀alkyl orheterocyclyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents; and the other variables are described asabove for Formula I.

In an embodiment of this tenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is aryl optionally substituted by oneor more independent G⁴¹ substituents; wherein R¹ is cyclobutyl,cyclopentyl, or cyclohexyl, any of which is optionally substituted byone or more independent G¹¹ substituents; and the other variables aredescribed as above for Formula I.

In an embodiment of this tenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is aryl optionally substituted by oneor more independent G⁴¹ substituents; wherein R¹ is cycloC₃₋₁₀alkyl orheterocyclyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —N²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this tenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is aryl optionally substituted by oneor more independent G⁴¹ substituents; wherein R¹ is cyclobutyl,cyclopentyl, or cyclohexyl, any of which is optionally substituted byone or more independent G¹¹ substituents;

wherein G^(11 is —OR) ²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²², —NR²²²¹R³³³¹(R^(2221a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an eleventh aspect of the present invention, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein Q¹ is phenyl substituted by said one to five independent G¹⁰substituents wherein at least one of said G¹⁰ substituents is—(X¹)_(n)—(Y¹)_(m)—R⁴; n is 1; X¹ is 3-(—O—); m is 0; R⁴ is phenyloptionally substituted by one or more independent G⁴¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this eleventh aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is phenyl optionally substituted byone or more independent G⁴¹ substituents; wherein R¹ is aryl,heteroaryl, cycloC₃₋₁₀alkyl, or heterocyclyl, any of which is optionallysubstituted by one or more independent G¹¹ substituents; and the othervariables are described as above for Formula I.

In an embodiment of this eleventh aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is phenyl optionally substituted byone or more independent G⁴¹ substituents; wherein R¹ is cycloC₃₋₁₀alkylor heterocyclyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents; and the other variables are described asabove for Formula I.

In an embodiment of this eleventh aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3-(—O—); m is 0; R⁴ is phenyl optionally substituted byone or more independent G⁴¹ substituents; wherein R¹ is cyclobutyl,cyclopentyl, or cyclohexyl, any of which is optionally substituted byone or more independent G¹¹ substituents; and the other variables aredescribed as above for Formula I.

In a twelfth aspect of the present invention, a compound is representedby Formula I, or a pharmaceutically acceptable salt thereof, wherein Q¹is phenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3- or 4-(—NH—); m is 1; Y¹ is —(—SO₂—); R⁴is aryloptionally substituted by one or more independent G⁴¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this twelfth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3- or 4-(—NH—); m is 1 Y¹ is —(—SO₂—); R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is aryl, heteroaryl, cycloC₃₋₁₀alkyl, or heterocyclyl, any ofwhich is optionally substituted by one or more independent G¹¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this twelfth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3- or 4-(—NH—); m is 1; Y¹ is —(—SO₂—); R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is cycloC₃₋₁₀alkyl or heterocyclyl, any of which isoptionally substituted by one or more independent G¹¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this twelfth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3- or 4-(—NH—); m is 1; Y¹ is —(—SO₂—); R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is cyclobutyl, cyclopentyl, or cyclohexyl, any of which isoptionally substituted by one or more independent G¹¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this twelfth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3- or 4-(—NH—); m is 1; Y¹ is —(—SO₂—); R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is cycloC₃₋₁₀alkyl or heterocyclyl, any of which isoptionally substituted by one or more independent G¹¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R²²²¹)_(j3a), —C(O)R²²²¹,—CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(2221a),—NR²²²¹, S(O_(j3a)R³³³¹, —C(═S)OR²²²¹, —C(═O)SR²²²¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), —NR²²²¹C(═NR³³³¹)OR^(2221a),—NR²²²¹C(═N³³³¹)SR^(2221a), —OC(═O)OR²²²¹, —OC(═O)NR²²²¹R³³³¹,—OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this twelfth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3- or 4-(—NH—); m is 1; Y¹ is —(—SO₂—); R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is cyclobutyl, cyclopentyl, or cyclohexyl, any of which isoptionally substituted by one or more independent G¹¹ substituents;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹)C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this twelfth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3- or 4-(—NH—); m is 1; Y¹ is —(—SO₂—); R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is cis- or trans- cyclobutyl substituted at the 3-position byG¹¹ wherein G¹¹ is —OH, —NH₂, —N(CH₃)₂, —NHAc, —NH(CO)NHCH₃,—NH(CO)OCH₃, —CH₂OH, —CH₂NH₂, —CH₂NHAc, CONH₂, —CH₂N(CH₃)₂,—CH₂NH(CO)NHMe, —CH₂NH(CO)OCH₃, CO₂CH₃, or CONHCH₃,; and the othervariables are described as above for Formula I.

In an embodiment of this twelfth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by said one to five independent G¹⁰ substituentswherein at least one of said G¹⁰ substituents is —(X¹)_(n)—(Y¹)_(m)—R⁴;n is 1; X¹ is 3- or 4-(—NH—); m is 1; Y¹ is —(—SO₂—); R⁴ is aryloptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is cis- or trans- cyclohexyl substituted at the 4-position byG¹¹ wherein G¹¹ is —OH, —NH₂, —N(CH₃)₂, —NHAc, —NH(CO)NHCH₃,—NH(CO)OCH₃, —CH₂OH, —CH₂NH₂, —CH₂NHAc, CONH₂, —CH₂N(CH₃)₂,—CH₂NH(CO)NHMe, —CH₂NH(CO)OCH₃, CO₂CH₃, or CONHCH₃; and the othervariables are described as above for Formula I.

In a thirteenth aspect of the present invention, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein Q¹ is aryl¹ substituted by one or more independent G¹⁰substituents and the other variables are described as above for FormulaI.

In an embodiment of this thirteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent by G¹⁰ substituents andthe other variables are described as above for Formula I.

In a fourteenth aspect of the present invention, a compound isrepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein Q¹ is aryl¹ substituted by one or more independent G¹⁰substituents, wherein the at least one G¹⁰ substituent is—(X¹)_(n)—(Y¹)_(m)—R⁴, and the other variables are described as abovefor Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents, whereinthe at least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴, and the othervariables are described as above for Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)—, 4-(O)—, 3-(NH)—, or 4-(NH)—; wherein Y¹ is —CH₂— or —(SO₂)—;wherein n and m are independently 0 or 1; and the other variables aredescribed as above for Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)— or 4-(O)—; wherein Y¹ is —CH₂—; n and m are each 1; and the othervariables are described as above for Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)— or 4-(O)—; wherein Y¹ is —CH₂—; wherein n and m are each 1;wherein R⁴ is aryl, C₀₋₁₀alkyl, or cycloC₃₋₁₀alkyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents; andthe other variables are described as above for Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)— or 4-(O)—; wherein Y¹ is —CH₂—; wherein n and m are each 1;wherein R⁴ is phenyl optionally substituted by one or more independentG⁴¹ substituents; and the other variables are described as above forFormula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)— or 4-(O)—; wherein Y¹ is —CH₂—; wherein n and m are each 1;wherein R⁴ is aryl, C₀₋₁₀alkyl, or cycloC₃₋₁₀alkyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is aryl, heteroaryl, cycloC₃₋₁₀alkyl, or heterocyclyl, any ofwhich is optionally substituted by G¹¹; and the other variables aredescribed as above for Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)— or 4-(O)—; Y¹ is —CH₂—; n and m are each 1; wherein R⁴is aryl,C₀₋₁₀alkyl, or cycloC₃₋₁₀alkyl, any of which is optionally substitutedby one or more independent G⁴¹ substituents; wherein R¹ iscycloC₃₋₁₀alkyl which is optionally substituted by G¹¹; and the othervariables are described as above for Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)—or 4-(O)—; wherein Y¹ is —CH₂—; wherein n and m are each 1;wherein R⁴ is phenyl optionally substituted by one or more independentG⁴¹ substituents; wherein R¹ is aryl, heteroaryl, cycloC₃₋₁₀alkyl, orheterocyclyl, any of which is optionally substituted by G¹¹; and theother variables are described as above for Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)— or 4-(O)—; wherein Y¹ is —CH₂—; wherein n and m are each 1;wherein R⁴is phenyl optionally substituted by one or more independentG⁴¹ substituents; wherein R¹ is cycloC₃₋₁₀alkyl which is optionallysubstituted by G¹¹; and the other variables are described as above forFormula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)— or 4-(O)—; wherein Y¹ is —CH₂—; n and m are each 1; wherein R⁴ isphenyl optionally substituted by one or more independent G⁴¹substituents; wherein R¹ is cyclobutyl, cyclopentyl, or cyclohexyl, anyof which is optionally substituted by G¹¹; and the other variables aredescribed as above for Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)— or 4-(O)—; wherein Y¹ is —CH₂—; wherein n and m are each 1;wherein R⁴ is phenyl optionally substituted by one or more independentG⁴¹ substituents; wherein R¹ is cis- or trans-cyclobutyl substituted atthe 3-position by G¹¹ or R¹ is cis- or trans-cyclohexyl substituted atthe 4-position by G¹¹; and the other variables are described as abovefor Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)— or 4-(O)—; wherein Y¹ is —CH₂—; n and m are each 1; wherein R⁴ isphenyl optionally substituted by one or more independent G⁴¹substituents; wherein R¹ is cis- or trans-cyclobutyl substituted at the3-position by G¹¹ wherein G¹¹ is —OH, —NH₂, —N(CH₃)₂, —NHAc,—NH(CO)NHCH₃, —NH(CO)OCH₃, —CH₂OH, —CH₂NH₂, —CH₂NHAc, CONH₂,—CH₂N(CH₃)₂, —CH₂NH(CO)NHMe, —CH₂NH(CO)OCH₃, CO₂CH₃, or CONHCH₃; and theother variables are described as above for Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)— or 4-(O)—; wherein Y¹ is —CH₂—; wherein n and m are each 1;wherein R⁴ is phenyl optionally substituted by one or more independentG⁴¹ substituents; wherein R¹ is cis- or trans-cyclohexyl substituted atthe 4-position by G¹¹ wherein G¹¹ is —OH, —NH₂, —N(CH₃)₂, —NHAc,—NH(CO)NHCH₃, —NH(CO)OCH₃, —CH₂OH, —CH₂NH₂, —CH₂NHAc, CONH₂,—CH₂N(CH₃)₂, —CH₂NH(CO)NHMe, —CH₂NH(CO)OCH₃, CO₂CH₃, or CONHCH₃; and theother variables are described as above for Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)— or 4-(O)—; wherein Y¹ is —CH₂—; wherein n and m are each 1;wherein R⁴ is aryl, C₀₋₁₀alkyl, or cycloC₃₋₁₀alkyl, any of which isoptionally substituted by one or more independent G⁴¹ substituents;wherein R¹ is cycloC₃₋₁₀alkyl which is optionally substituted by G¹¹;

wherein G¹¹ is —OR²¹, —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(2221a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein X¹ is3-(O)— or 4-(O)—; wherein Y¹ is —CH₂—; wherein n and m are each 1;wherein R⁴ is phenyl optionally substituted by one or more independentG⁴¹ substituents; wherein R¹ is aryl, heteroaryl, cycloC₃₋₁₀alkyl, orheterocyclyl, any of which is optionally substituted by G¹¹;

wherein G¹¹ is —OR², —NR²¹R³¹, —CO₂R²¹, —C(O)R²¹, —CONR²¹R³¹,—NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹, —NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹,—OC(═O)OR²¹, —OC(═O)NR²¹R³¹, C₀₋₁₀alkyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl,any of which is optionally substituted with one or more independenthalo, oxo, —CF₃, —OCF₃, —OR²²²¹, —NR²²²¹R³³³¹(R^(222a))_(j3a),—C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j3a)R²²²¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹, —C(═S)OR²²²¹,—C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹,—OC(═O)NR²²²¹R³³³¹, —OC(═O)SR²²²¹, —SC(═O)OR²²²¹, or —SC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein R¹ isrepresented by the structural formula:

wherein Z² is a heterocyclyl containing a N substituted by G¹¹; and theother variables are described as above for Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴; wherein R¹ isrepresented by the structural formula:

wherein G¹¹ is —C(O)R²¹, —CO₂R²¹, —ONR²¹R³¹, —SO₂NR²¹R³¹, —S(O)_(j3)R³¹,C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionally substituted with one or more independent oxo, —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹, —(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or —OC(═O)NR²²²¹R³³³¹substituents;

or G¹¹ is aryl-C₀₋₁₀alkyl or hetaryl-C₀₋₁₀alkyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or —OC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴;

wherein R¹ is represented by the structural formula:

wherein G¹¹ is —C(O)R²¹, —CO₂R²¹, —CONR²¹R³¹, —SO₂NR²¹R³¹,—S(O)_(j3)R³¹, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionally substituted with one or more independent oxo, —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or —OC(═O)NR²²²¹R³³³¹substituents; and the other variables are described as above for FormulaI.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴;

wherein R¹ is represented by the structural formula:

wherein G¹¹ is —C(O)R²¹, —CO₂R²¹, —CONR²¹R³¹, —SO₂NR²¹R³¹,—S(O)_(j3)R³¹, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionally substituted with one or more independent oxo, —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR²²²¹R³³³¹, —NR²²²¹S(O)_(j3a)R³³³¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or —OC(═O)NR²²²¹R³³³¹substituents;

or G¹¹ aryl-C₀₋₁₀alkyl or hetaryl-C₀₋₁₀alkyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR²²²¹R³³³¹,—NR²²²¹S(O)_(j3a)R³³³¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or—OC(═O)NR²²²¹R³³³¹ substituents; and the other variables are describedas above for Formula I.

In an embodiment of this fourteenth aspect, a compound is represented byFormula I, or a pharmaceutically acceptable salt thereof, wherein Q¹ isphenyl substituted by one or more independent G¹⁰ substituents; whereinat least one G¹⁰ substituent is —(X¹)_(n)—(Y¹)_(m)—R⁴;

wherein R¹ is represented by the structural formula:

wherein G¹¹ is —C(O)R²¹, —CO₂R²¹, —CONR²¹R³¹, —SO₂NR²¹R³¹,—S(O)_(j3)R³¹, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionally substituted with one or more independent oxo, —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR²²²¹R³³³¹, —NR²²²¹S(O)_(j3a)R³³³¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or —OC(═O)NR²²²¹R³³³¹substituents; and the other variable are described as above for FormulaI.

The present invention includes the following compounds:

-   5-(3-benzyloxy-2-fluoro-phenyl)-7-cyclobutyl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-cyclobutyl-imidazo[5,1-f][1,2,4]triazin-4-ylamine-   3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutanone,-   3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutanol,-   3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl-]1-methyl-cyclobutanol,-   3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-1-ethyl-cyclobutanol,-   5-(3-Benzyloxy-phenyl)-7-(3-methylamino-cyclobutyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(3-dimethylamino-cyclobutyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   7-(3-Azetidin-1-yl-cyclobutyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(3-piperidin-1-yl-cyclobutyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutyl}-acetamide,-   {3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutyl}-carbamic    acid methyl ester,-   1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutyl}-3methyl-urea,-   N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutyl}-methanesulfonamide,-   7-Azetidin-3-yl-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-azetidin-1-yl}-ethanone,-   {3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutyl}-methanol,-   5-(3-Benzyloxy-phenyl)-7-(3-dimethylaminomethyl-cyclobutyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(3-diethylaminomethyl-cyclobutyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   7-(3-Azetidin-1-ylmethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(3-piperidin-1-ylmethyl-cyclobutyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutanecarboxylic    acid amide,-   5-(3-Benzyloxy-phenyl)-7-cyclohexyl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanone,-   4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanol,-   4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-1-methyl-cyclohexanol,-   4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-1-ethyl-cyclohexanol,-   4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic    acid methyl ester,-   4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic    acid amide,-   4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic    acid methylamide,-   {4-[4-Amino-5-(3    -benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexyl}-methanol,-   7-(4-Aminomethyl-cyclohexyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(4-dimethylaminomethyl-cyclohexyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   7-(4-Azetidin-1-ylmethyl-cyclohexyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(4-piperidin-1-ylmethyl-cyclohexyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-piperidin-4-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   1-{4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-piperidin-1-yl}-ethanone,-   5-(3-Benzyloxy-phenyl)-7-cyclopentyl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentanecarboxylic    acid methyl ester,-   3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentanecarboxylic    acid amide,-   3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentanecarboxylic    acid methylamide,-   {3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentyl}-methanol,-   7-(3-Aminomethyl-cyclopentyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(3-ethylaminomethyl-cyclopentyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   7-(3-Azetidin-1-ylmethyl-cyclopentyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(3-pyrrolidin-1-ylmethyl-cyclopentyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(3-piperidin-1-ylmethyl-cyclopentyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentylmethyl}-acetamide,-   {3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentylmethyl}-carbamic    acid methyl ester,-   1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentylmethyl}-3-methyl-urea,-   3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentanone,-   3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentanol,-   7-(3-Amino-cyclopentyl)-5-(3    -benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(3-dimethylamino-cyclopentyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   7-(3-Azetidin-1-yl-cyclopentyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(3-pyrrolidin-1-yl-cyclopentyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(3-piperidin-1-yl-cyclopentyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-phenyl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzoic    acid methyl ester,-   4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzamide,-   4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-N-methyl-benzamide,-   {4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl-]phenyl}-methanol,-   7-(4-Aminomethyl-phenyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(4-dimethylaminomethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   N-{4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzyl}-acetamide,-   {4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzyl}-carbamic    acid methyl ester,-   1-{4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzyl}-3-methyl-urea,-   5-(3-Benzyloxy-phenyl)-7-(4-dimethylaminomethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   7-(4-Azetidin-1-ylmethyl-phenyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(4-pyrrolidin-1-ylmethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(4-piperidin-1-ylmethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzoic    acid methyl ester,-   3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzamide,-   3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-N-methyl-benzamide,-   {3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-phenyl}-methanol,-   7-(3-Aminomethyl-phenyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzyl}-acetamide,-   {3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzyl}-carbamic    acid methyl ester,-   1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7yl]-benzyl}-3-methyl-urea,-   N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzyl}-methanesulfonamide,-   5-(3-Benzyloxy-phenyl)-7-(3-dimethylaminomethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(3-diethylaminomethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   7-(3-Azetidin-1-ylmethyl-phenyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(3-pyrrolidin-1-ylmethyl-phenyl)-imidazo[5,1-f][1,2,4triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(3-piperidin-1-ylmethyl-phenyl)-imidazo[5,1-f][1,2,4triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-pyridin-4-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-oxazol-2-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-thiophen-3-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-thiophen-2-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-thiazol-5-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-thiazol-2-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(1H-imidazol-2-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,-   5-(3-Benzyloxy-phenyl)-7-(1H-imidazol-4-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,    or a pharmaceutically acceptable salt thereof.

The present invention includes a method of inhibiting protein kinaseactivity comprising administering a compound of Formula I or apharmaceutically acceptable salt thereof.

The present invention includes the method of inhibiting protein kinaseactivity comprising administering a compound of Formula I or apharmaceutically acceptable salt thereof wherein said protein kinase isIGF-1R.

The present invention includes the method of inhibiting protein kinaseactivity comprising administering a compound of Formula I or apharmaceutically acceptable salt thereof wherein the activity of saidprotein kinase affects hyperproliferative disorders.

The present invention includes the method of inhibiting protein kinaseactivity comprising administering a compound of Formula I or apharmaceutically acceptable salt thereof wherein the activity of saidprotein kinase influences angiogenesis, vascular permeability, immuneresponse, cellular apoptosis, tumor growth, or inflammation.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein said protein kinase is IGF-1R.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity is ahyperproliferative disorder.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the activity of said protein kinase influencesangiogenesis, vascular permeability, immune response, cellularapoptosis, tumor growth, or inflammation.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the protein kinase is a protein serine/threonine kinaseor a protein tyrosine kinase.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity is oneor more ulcers.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity is oneor more ulcers wherein the ulcer or ulcers are caused by a bacterial orfungal infection; or the ulcer or ulcers are Mooren ulcers; or the ulceror ulcers are a symptom of ulcerative colitis.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity isLyme disease, sepsis or infection by Herpes simplex, Herpes Zoster,human immunodeficiency virus, parapoxvirus, protozoa, or toxoplasmosis.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity is vonHippel Lindau disease, pemphigoid, psoriasis, Paget's disease, orpolycystic kidney disease.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity isfibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome,Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthma,exudtaes, ascites, pleural effusions, pulmonary edema, cerebral edema oredema following burns, trauma, radiation, stroke, hypoxia, or ischemia.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity isovarian hyperstimulation syndrome, preeclainpsia, menometrorrhagia, orendometriosis.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase-activity ischronic inflammation, systemic lupus, glomerulonephritis, synovitis,inflammatory bowel disease, Crohn's disease, glomerulonephritis,rheumatoid arthritis and osteoarthritis, multiple sclerosis, or graftrejection.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity issickle cell anemia.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity is anocular condition.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity is anocular condition wherein the ocular condition is ocular or macularedema, ocular neovascular disease, seleritis, radial keratotomy,uveitis, vitritis, myopia, optic pits, chronic retinal detachment,post-laser treatment complications, conjunctivitis, Stargardt's disease,Eales disease, retinopathy, or macular degeneration.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity is acardiovascular condition.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity isatherosclerosis, restenosis, ischemia/reperfusion injury, vascularocclusion, venous malformation, or carotid obstructive disease.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity iscancer.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity iscancer wherein the cancer is a solid tumor, a sarcoma, fibrosarcoma,osteoma, melanoma, retinoblastoma, a rhabdomyosarcoma, glioblastoma,neuroblastoma, teratocarcinoma, an hematopoietic malignancy, ormalignant ascites.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity iscancer wherein the cancer is Kaposi's sarcoma, Hodgkin's disease,lymphoma, myeloma, or leukemia.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity isCrow-Fukase (POEMS) syndrome or a diabetic condition.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the condition mediated by protein kinase activity isCrow-Fukase (POEMS) syndrome or a diabetic condition wherein thediabetic condition is insulin-dependent diabetes mellitus glaucoma,diabetic retinopathy, or microangiopathy.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof wherein the protein kinase activity is involved in T cellactivation, B cell activation, mast cell degranulation, monocyteactivation, signal transduction, apoptosis, the potentiation of aninflammatory response or a combination thereof.

The present invention includes the use of a compound of Formula I, or apharmaceutically acceptable salt thereof, for the preparation of apharmaceutical composition for the treatment of a disease which respondsto an inhibition of the IGF-1R-dependent cell proliferation.

The present invention includes the use of a compound of Formula I, or apharmaceutically acceptable salt thereof, for the preparation of apharmaceutical composition for the treatment of a disease which respondsto an inhibition of the IGF-1R tyrosine kinase.

The present invention includes the a method of inhibiting protein kinaseactivity comprising administering a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present invention includes a method of treating a patient having acondition which is mediated by protein kinase activity, said methodcomprising administering to the patient a therapeutically effectiveamount of a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

Unless otherwise stated, the connections of compound name moieties areat the rightmost recited moiety. That is, the substituent name startswith a terminal moiety, continues with any bridging moieties, and endswith the connecting moiety. For example, hetarylthioC₁₋₄alkyl has aheteroaryl group connected through a thio sulfur to a C₁₋₄ alkyl thatconnects to the chemical species bearing the substituent.

As used herein, for example, “C₀₋₄alkyl” is used to mean an alkyl having0-4 carbons—that is, 0, 1, 2, 3, or 4 carbons in a straight or branchedconfiguration. An alkyl having no carbon is hydrogen when the alkyl is aterminal group. An alkyl having no carbon is a direct bond when thealkyl is a bridging (connecting) group.

In all embodiments of this invention, the term “alkyl” includes bothbranched and straight chain alkyl groups. Typical alkyl groups aremethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, isooctyl, nonyl,decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl andthe like.

The term “acyl” refers to an alkylketo or arylketo group, for example,formyl, acetyl, butyryl, benzoyl, and the like.

The term “halo” refers to fluoro, chloro, bromo, or iodo.

The term “haloalkyl” refers to an alkyl group substituted with one ormore halo groups, for example, chloromethyl, 2-bromoethyl, 3-iodopropyl,trifluoromethyl, perfluoropropyl, 8-chlorononyl, and the like.

The term “cycloalkyl” refers to a cyclic aliphatic ring structure,optionally substituted with alkyl, hydroxy and halo, such ascyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl,2-hydroxycyclopentyl, cyclohexyl, 4-chlorocyclohexyl, cycloheptyl,cyclooctyl, and the like.

The term “alkylcarbonyloxyalkyl” refers to an ester moiety, for example,acetoxymethyl, n-butyryloxyethyl, and the like.

The term “alkynylcarbonyl” refers to an alkynylketo functionality, forexample, propynoyl and the like.

The term “hydroxyalkyl” refers to an alkyl group substituted with one ormore hydroxy groups, for example, hydroxymethyl, 2,3-dihydroxybutyl, andthe like.

The term “alkylsulfonylalkyl” refers to an alkyl group substituted withan alkylsulfonyl moiety, for example, mesylmethyl,isopropylsulfonylethyl, and the like.

The term “alkylsulfonyl” refers to a sulfonyl moiety substituted with analkyl group, for example, mesyl, n-propylsulfonyl, and the like.

The term “monoalkylaminoalkyl” refers to an alkyl group substituted withan amine moiety which is itself substituted with one alkyl group, forexample, N-methylaminoethyl and the like.

The term “dialkylaminoalkyl” refers to an alkyl group substituted withan amine moiety which is itself substituted with two alkyl groups, forexample, N,N-dimethylaminoethyl, N-ethyl-N-methylaminomethyl, and thelike.

The term “monoarylaminoalkyl” refers to an alkyl group substituted withan amine moiety which is itself substituted with one aryl group, forexample, N-phenylaminoethyl and the like.

The term “diarylaminoalkyl” refers to an alkyl group substituted with anamine moiety which is itself substituted with two aryl groups, forexample, N,N-diphenylaminoethyl and the like.

The term “monohetarylaminoalkyl” or “monoheteroarylaminoalkyl” refers toan alkyl group substituted with an amine moiety which is itselfsubstituted with one hetaryl group.

The term “dihetarylaminoalkyl” or “diheteroarylaminoalkyl” refers to analkyl group substituted with an amine moiety which is itself substitutedwith two hetaryl groups.

The term “monoalkylaminocarbonyl” refers to an amide group substitutedwith one alkyl group, for example, N-methylamido and the like.

The term “dialkylaminocarbonyl” refers to an amide group substitutedwith two alkyl groups, for example, N,N-dimethylamido,N-methyl-N-ethylamido and the like.

The term “monoarylaminocarbonyl” refers to an amide group substitutedwith one aryl group, for example, N-phenylamido and the like.

The term “diarylaminocarbonyl” refers to an amide group substituted withtwo aryl groups, for example, N,N-diphenylamido and the like.

The term “alkylarylaminocarbonyl” refers to an amide group substitutedwith one alkyl and one aryl group, for example, N-methyl-N-phenylamidoand the like.

The term “monohetarylaminocarbonyl” or “monoheteroarylaminocarbonyl”refers to an amide group substituted with one hetaryl group.

The term “dihetarylaminocarbonyl” or “diheteroarylaminocarbonyl” refersto an amide group substituted with two hetaryl groups.

The term “alkylhetarylaminocarbonyl” or “alkylheteroarylaminocarbonyl”refers to an amide group substituted with one alkyl and one hetarylgroup.

The term “acetylaminoalkyl” refers to an alkyl group substituted with anamide moiety, for example, acetylaminomethyl and the like.

The term “acetylaminoalkenyl” refers to an alkenyl group substitutedwith an amide moiety, for example, 2-(acetylamino)vinyl and the like.

The term “alkenyl” refers to an ethylenically unsaturated hydrocarbongroup, straight or branched chain, having at least one ethylenic bond,for example, vinyl, allyl, 1-butenyl, 2-butenyl, isopropenyl,2-pentenyl, and the like.

The term “haloalkenyl” refers to an alkenyl group substituted with oneor more halo groups.

The term “cycloalkenyl” refers to a cyclic aliphatic ring structurehaving at least one endocyclic ethylenic bond, optionally substitutedwith one or more independent substituents such as alkyl, hydroxy, orhalo. Examples of cycloalkenyls include, but are not limited to,methylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl,cyclohexenyl, 1,4-cyclohexadienyl, and the like.

The term “alkynyl” refers to an unsaturated hydrocarbon group, straightor branched, having at least one acetylenic bond, for example, ethynyl,propargyl, and the like.

The term “haloalkynyl” refers to an alkynyl group substituted with oneor more halo groups.

The term “alkylcarbonyl” refers to an alkylketo functionality, forexample, acetyl, n-butyryl, and the like.

The term “alkenylcarbonyl” refers to an alkenylketo functionality, forexample, propenoyl and the like.

The term “aryl” refers to phenyl or naphthyl which may be optionallysubstituted by one or more independent substituents. Typical arylsubstituents include, but are not limited to, phenyl, 4-chlorophenyl,4-fluorophenyl, 4-bromophenyl, 3-nitrophenyl, 2-methoxyphenyl,2-methylphenyl, 3-methyphenyl, 4-methylphenyl, 4-ethylphenyl,2-methyl-3-methoxyphenyl, 2,4-dibromophenyl, 3,5-difluorophenyl,3,5-dimethylphenyl, 2,4,6-trichlorophenyl, 4-methoxyphenyl, naphthyl,2-chloronaphthyl, 2,4-dimethoxyphenyl, 4-(trifluoromethyl)phenyl, and2-iodo-4-methylphenyl.

The term “aryl¹” refers to phenyl which may be optionally substituted byone or more independent substituents. Typical aryl¹ substituentsinclude, but are not limited to, phenyl, 4-chlorophenyl, 4-fluorophenyl,4-bromophenyl, 2-methoxyphenyl, 2-methylphenyl, 4-methylphenyl,4-ethylphenyl, 2,4-dibromophenyl, 2,4,6-trichlorophenyl,4-methoxyphenyl, 2,4-dimethoxyphenyl, 4-(trifluoromethyl)phenyl, and2-iodo-4-methylphenyl.

The terms “heteroaryl” or “hetaryl” refer to a substituted orunsubstituted 5- or 6-membered unsaturated ring containing one, two,three, or four heteroatoms, preferably one or two heteroatomsindependently selected from oxygen, nitrogen, and sulfur or to asubstituted or unsubstituted bicyclic unsaturated ring system containingup to 10 atoms including at least one heteroatom selected from oxygen,nitrogen, and sulfur. Examples of hetaryls include, but are not limitedto, 2-, 3-, or 4-pyridinyl, pyrazinyl, 2-, 4-, or 5-pyrimidinyl,pyridazinyl, triazolyl, tetrazolyl, imidazolyl, 2- or 3-thienyl, 2- or3-furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzimidazolyl,benzotriazolyl, benzofuranyl, and benzothienyl.

The terms “heteroaryl¹” or “hetaryl¹” refer to a substituted orunsubstituted 5- or 6-membered unsaturated ring containing one, two,three, or four heteroatoms, preferably one or two heteroatomsindependently selected from oxygen, nitrogen and sulfur. Examples ofhetaryl's include, but are not limited to, 2-, 3- or 4-pyridinyl,pyrazinyl, 2-, 4-, or 5-pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl,imidazolyl, 2- or 3-thienyl, 2- or 3-furyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. Theheterocyclic ring may be optionally substituted with up to twosubstituents.

The terms “aryl-alkyl” or “arylalkyl” or “aralkyl” are used to describea group wherein the alkyl chain can be branched or straight chain withthe aryl portion, as defined hereinbefore, forming a bridging portion ofthe aryl-alkyl moiety. Examples of aryl-alkyl groups include, but arenot limited to, optionally substituted benzyl, phenethyl, phenpropyl andphenbutyl such as 4-chlorobenzyl, 2,4-dibromobenzyl, 2-methylbenzyl,2-(3-fluorophenyl)ethyl, 2-(4-methylphenyl)ethyl,2-(4-(trifluoromethyl)phenyl)ethyl, 2-(2-methoxyphenyl)ethyl,2-(3-nitrophenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl,2-(3,5-dimethoxyphenyl)ethyl, 3-phenylpropyl, 3-(3-chlorophenyl)propyl,3-(2-methylphenyl)propyl, 3-(4-methoxyphenyl)propyl,3-(4-(trifluoromethyl)phenyl)propyl, 3-(2,4-dichlorophenyl)propyl,4-phenylbutyl, 4-(4-chlorophenyl)butyl, 4-(2-methylphenyl)butyl,4-(2,4-dichlorophenyl)butyl, 4-(2-methoxphenyl)butyl, and10-phenyldecyl.

The terms “aryl-Cycloalkyl” or “arylcycloalkyl” are used to describe agroup wherein the aryl group is attached to a cycloalkyl group, forexample, phenylcyclopentyl and the like.

The terms “aryl-alkenyl” or “arylalkenyl” are used to describe a groupwherein the alkenyl chain can be branched or straight chain with thearyl portion, as defined hereinbefore, forming a bridging portion of thearalkenyl moiety, for example, styryl (2-phenylvinyl), phenpropenyl, andthe like.

The terms “aryl-alkynyl” or “arylalkynyl” are used to describe a groupwherein the alkynyl chain can be branched or straight chain with thearyl portion, as defined hereinbefore, forming a bridging portion of thearyl-alkynyl moiety, for example, 3-phenyl-1-propynyl and the like.

The terms “aryl-oxy” or “aryloxy” are used to describe a terminal arylgroup attached to a bridging oxygen atom. Typical aryl-oxy groupsinclude phenoxy, 3,4-dichlorophenoxy, and the like.

The terms “aryl-oxyalkyl” or “aryloxyalkyl” are used to describe a groupwherein an alkyl group is substituted with an aryl-oxy group, forexample, pentafluorophenoxymethyl and the like.

The terms “hetaryl-oxy” or “heteroaryl-oxy” or “hetaryloxy” or“heteroaryloxy” are used to describe a terminal hetaryl group attachedto a bridging oxygen atom. Typical hetaryl-oxy groups include4,6-dimethoxypyrimidin-2-yloxy and the like.

The terms “hetarylalkyl” or “heteroarylalkyl” or “heteroaralkyl” or“hetaryl-alkyl” or “heteroaryl-alkyl” are used to describe a groupwherein the alkyl chain can be branched or straight chain with theheteroaryl portion, as defined hereinbefore, forming a bridging portionof the heteroaralkyl moiety, for example, 3-furylmethyl, thenyl,furfuryl, and the like.

The terms “hetarylalkenyl” or “heteroarylalkenyl” or “hetaryl-alkenyl”or “heteroaryl-alkenyl” are used to describe a group wherein the alkenylchain can be branched or straight chain with the heteroaryl portion, asdefined hereinbefore, forming a bridging portion of the heteroaralkenylmoiety, for example, 3-(4-pyridyl)-1-propenyl.

The terms “hetarylalkynyl” or “heteroarylalkynyl” or “hetaryl-alkynyl”or “heteroaryl-alkynyl” are used to describe a group wherein the alkynylchain can be branched or straight chain with the heteroaryl portion, asdefined hereinbefore, forming a bridging portion of the heteroaralkynylmoiety, for example, 4-(2-thienyl)-1-butynyl.

The term “heterocyclyl” refers to a substituted or unsubstituted 3-10membered saturated ring containing one, two, or three heteroatoms,preferably one or two heteroatoms independently selected from oxygen,nitrogen, and sulfur or to a substituted or unsubstituted bicyclic ringsystem containing up to 10 atoms including at least one heteroatomselected from oxygen, nitrogen, and sulfur wherein the ring containingthe heteroatom is saturated. The heterocyclyl may be optionallysubstituted by one or more independent substituents. Examples ofheterocyclyls include, but are not limited to, oxetane, azetidine,aziridene, tetrahydrofuranyl, tetrahydrofuryl, azetidinyl, pyrrolidinyl,piperidinyl, pyranyl, tetrahydropyranyl, thiolanyl, morpholinyl,piperazinyl, dioxolanyl, dioxanyl, indolinyl, 5-methyl-6-chromanyl, and

wherein Z² is a heterocyclyl containing a N substituted by G¹¹.

The terms “heterocyclylalkyl” or “heterocyclyl-alkyl” are used todescribe a group wherein the alkyl chain can be branched or straightchain with the heterocyclyl portion, as defined hereinabove, forming abridging portion of the heterocyclylalkyl moiety, for example,3-piperidinylmethyl and the like.

The terms “heterocyclylalkenyl” or “heterocyclyl-alkenyl” or“heterocycloalkenyl” or “heterocyclo-alkenyl” are used to describe agroup wherein the alkenyl chain can be branched or straight chain withthe heterocyclyl portion, as defined hereinbefore, forming a bridgingportion of the heterocyclylalkenyl moiety, for example,2-morpholinyl-1-propenyl.

The terms “heterocyclylalkynyl” or “heterocyclyl-alkynyl” are used todescribe a group wherein the alkynyl chain can be branched or straightchain with the heterocyclyl portion, as defined hereinbefore, forming abridging portion of the heterocyclylalkynyl moiety, for example,2-pyrrolidinyl-1-butynyl.

The term “carboxylalkyl” includes both branched and straight chain alkylgroups as defined hereinbefore attached to a carboxyl (—COOH) group.

The term “carboxylalkenyl” includes both branched and straight chainalkenyl groups as defined hereinbefore attached to a carboxyl (—COOH)group.

The term “carboxylalkynyl” includes both branched and straight chainalkynyl groups as defined hereinbefore attached to a carboxyl (—COOH)group.

The term “carboxylcycloalkyl” refers to a carboxyl (—COOH) groupattached to a cyclic aliphatic ring structure as defined hereinbefore.

The term “carboxylcycloalkenyl” refers to a carboxyl (—COOH) groupattached to a cyclic aliphatic ring structure having 1 or 2 ethylenicbonds as defined hereinbefore.

The terms “cycloalkylalkyl” or “cycloalkyl-alkyl” refer to a cycloalkylgroup as defined hereinbefore attached to an alkyl group, for example,cyclopropylmethyl, cyclohexylethyl, and the like.

The terms “cycloalkylalkenyl” or “cycloalkyl-alkenyl” refer to acycloalkyl group as defined hereinbefore attached to an alkenyl group,for example, cyclohexylvinyl, cycloheptylallyl, and the like.

The terms “cycloalkylalkynyl” or “cycloalkyl-alkynyl” refer to acycloalkyl group as defined hereinbefore attached to an alkynyl group,for example, cyclopropylpropargyl, 4-cyclopentyl-2-butynyl, and thelike.

The terms “cycloalkenylalkyl” or “cycloalkenyl-alkyl” refer to acycloalkenyl group as defined hereinbefore attached to an alkyl group,for example, 2-(cyclopenten-1-yl)ethyl and the like.

The terms “cycloalkenylalkenyl” or “cycloalkenyl-alkenyl” refer to acycloalkenyl group as defined hereinbefore attached to an alkenyl group,for example, 1-(cyclohexen-3-yl)allyl and the like.

The terms “cycloalkenylalkynyl” or “cycloalkenyl-alkynyl” refer to acycloalkenyl group as defined hereinbefore attached to an alkynyl group,for example, 1-(cyclohexen-3-yl)propargyl and the like.

The term “carboxylcycloalkylalkyl” refers to a carboxyl (—COOH) groupattached to the cycloalkyl ring portion of a cycloalkylalkyl group asdefined hereinbefore.

The term “carboxylcycloalkylalkenyl” refers to a carboxyl (—COOH) groupattached to the cycloalkyl ring portion of a cycloalkylalkenyl group asdefined hereinbefore.

The term “carboxylcycloalkylalkynyl” refers to a carboxyl (—COOH) groupattached to the cycloalkyl ring portion of a cycloalkylalkynyl group asdefined hereinbefore.

The term “carboxylcycloalkenylalkyl” refers to a carboxyl (—COOH) groupattached to the cycloalkenyl ring portion of a cycloalkenylalkyl groupas defined hereinbefore.

The term “carboxylcycloalkenylalkenyl” refers to a carboxyl (—COOH)group attached to the cycloalkenyl ring portion of a cycloalkenylalkenylgroup as defined hereinbefore.

The term “carboxylcycloalkenylalkynyl” refers to a carboxyl (—COOH)group attached to the cycloalkenyl ring portion of a cycloalkenylalkynylgroup as defined hereinbefore.

The term “bicycloalkyl” refers to a cyclic aliphatic group having tworings, wherein said rings share one or two carbon atoms, which may beoptionally substituted by one or more independent substituents. Examplesof bicycloalkyls include, but are not limited to, spiropentane,norbornyl, bicyclo[3.1.0]hexyl, spiro[4.4]nonyl, and the like.

The term “heterobicycloalkyl” refers to a cyclic aliphatic group havingtwo rings, wherein said rings share one or two atoms, and wherein atleast one of the rings contains at least one heteroatom and which may beoptionally substituted by one or more independent substituents. Examplesof heterobicycloalkyls include, but are not limited to,3-aza-bicyclo[4.1.0]heptanyl, 1,4-dioxaspiro[4.4]nonyl, and the like.

The term “alkoxy” includes both branched and straight chain terminalalkyl groups attached to a bridging oxygen atom. Typical alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, and thelike.

The term “haloalkoxy” refers to an alkoxy group substituted with one ormore halo groups, for example, chloromethoxy, trifluoromethoxy,difluoromethoxy, perfluoroisobutoxy, and the like.

The term “alkoxyalkoxyalkyl” refers to an alkyl group substituted withan alkoxy moiety which is in turn substituted with a second alkoxymoiety, for example, methoxymethoxymethyl, isopropoxymethoxyethyl, andthe like.

The term “alkylthio” includes both branched and straight chain alkylgroups attached to a bridging sulfur atom, for example, methylthio andthe like.

The term “haloalkylthio” refers to an alkylthio group substituted withone or more halo groups, for example, trifluoromethylthio and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group, for example, isopropoxymethyl.

The term “alkoxyalkenyl” refers to an alkenyl group substituted with analkoxy group, for example, 3-methoxyallyl.

The term “alkoxyalkynyl” refers to an alkynyl group substituted with analkoxy group, for example, 3-methoxypropargyl.

The term “alkoxycarbonylalkyl” refers to a straight chain or branchedalkyl substituted with an alkoxycarbonyl, for exampleethoxycarbonylmethyl, 2-(methoxycarbonyl)propyl and the like.

The term “alkoxycarbonylalkenyl” refers to a straight chain or branchedalkenyl as defined hereinbefore substituted with an alkoxycarbonyl, forexample, 4-(ethoxycarbonyl)-2-butenyl and the like.

The term “alkoxycarbonylalkynyl” refers to a straight chain or branchedalkynyl as defined hereinbefore substituted with an alkoxycarbonyl, forexample, 4-(ethoxycarbonyl)-2-butynyl and the like.

The term “haloalkoxyalkyl” refers to a straight chain or branched alkylas defined hereinbefore substituted with a haloalkoxy, for example,2-chloroethoxymethyl, trifluoromethoxymethyl, and the like.

The term “haloalkoxyalkenyl” refers to a straight chain or branchedalkenyl as defined hereinbefore substituted with a haloalkoxy, forexample, 4-(chloromethoxy)-2-butenyl and the like.

The term “haloalkoxyalkynyl” refers to a straight chain or branchedalkynyl as defined hereinbefore substituted with a haloalkoxy, forexample, 4-(2-fluoroethoxy)-2-butynyl and the like.

The term “alkylthioalkyl” or “alkylthio-alkyl” refers to a straightchain or branched alkyl as defined hereinbefore substituted with analkylthio group, for example, methylthiomethyl, 3-(isobutylthio)heptyl,and the like.

The term “alkylthioalkenyl” refers to a straight chain or branchedalkenyl as defined hereinbefore substituted with an alkylthio group, forexample, 4-(methylthio)-2-butenyl and the like.

The term “alkylthioalkynyl” refers to a straight chain or branchedalkynyl as defined hereinbefore substituted with an alkylthio group, forexample, 4-(ethylthio)-2-butynyl and the like.

The term “haloalkylthioalkyl” refers to a straight chain or branchedalkyl as defined hereinbefore substituted with an haloalkylthio group,for example, 2-chloroethylthiomethyl, trifluoromethylthiomethyl, and thelike.

The term “haloalkylthioalkenyl” refers to a straight chain or branchedalkenyl as defined hereinbefore substituted with an haloalkylthio group,for example, 4-(chloromethylthio)-2-butenyl and the like.

The term “haloalkylthioalkynyl” refers to a straight chain or branchedalkynyl as defined hereinbefore substituted with a haloalkylthio group,for example, 4-(2-fluoroethylthio)-2-butynyl and the like.

The term “dialkoxyphosphorylalkyl” refers to two straight chain orbranched alkoxy groups as defined hereinbefore attached to a pentavalentphosphorous atom, containing an oxo substituent, which is in turnattached to an alkyl, for example, diethoxyphosphorylmethyl.

The term “oligomer” refers to a low-molecular weight polymer, whosenumber average molecular weight is typically less than about 5000 g/mol,and whose degree of polymerization (average number of monomer units perchain) is greater than one and typically equal to or less than about 50.

Compounds described herein contain one or more asymmetric centers andmay thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable salts thereofFurther, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

The invention also encompasses a pharmaceutical composition that iscomprised of a compound of Formula I in combination with apharmaceutically acceptable carrier.

Preferably the composition is comprised of a pharmaceutically acceptablecarrier and a non-toxic therapeutically effective amount of a compoundof Formula I as described above (or a pharmaceutically acceptable saltthereof).

Moreover, within this preferred embodiment, the invention encompasses apharmaceutical composition for the treatment of disease by inhibitingkinases, comprising a pharmaceutically acceptable carrier and anon-toxic therapeutically effective amount of compound of Formula I asdescribed above (or a pharmaceutically acceptable salt thereof).

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium slats. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N′,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, formic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Preferred are citric, hydrobromic, formic, hydrochloric, maleic,phosphoric, sulfuric and tartaric acids. Particularly preferred areformic and hydrochloric acid.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula I (or a pharmaceutically acceptable saltthereof) as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In practice, the compounds represented by Formula I, or a prodrug, or ametabolite, or a pharmaceutically acceptable salts thereof, of thisinvention can be combined as the active ingredient in intimate admixturewith a pharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending on the form of preparation desired for administration. e.g.,oral or parenteral (including intravenous). Thus, the pharmaceuticalcompositions of the present invention can be presented as discrete unitssuitable for oral administration such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient.Further, the compositions can be presented as a powder, as granules, asa solution, as a suspension in an aqueous liquid, as a non-aqueousliquid, as an oil-in-water emulsion, or as a water-in-oil liquidemulsion. In addition to the common dosage forms set out above, thecompound represented by Formula I, or a pharmaceutically acceptable saltthereof, may also be administered by controlled release means and/ordelivery devices. The compositions may be prepared by any of the methodsof pharmacy. In general, such methods include a step of bringing intoassociation the active ingredient with the carrier that constitutes oneor more necessary ingredients. In general, the compositions are preparedby uniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound, or apharmaceutically acceptable salt, of Formula I. The compounds of FormulaI, or pharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents, and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.05 mg to about 5 g of the activeingredient and each cachet or capsule preferably containing from about0.05 mg to about 5 g of the active ingredient.

For example, a formulation intended for the oral administration tohumans may contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or a pharmaceutically acceptable saltthereof, via conventional processing methods. As an example, a cream orointment is prepared by admixing hydrophilic material and water,together with about 5 wt % to about 10 wt % of the compound, to producea cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

Generally, dosage levels on the order of from about 0.01 mg/kg to about150 mg/kg of body weight per day are useful in the treatment of theabove-indicated conditions, or alternatively about 0.5 mg to about 7 gper patient per day. For example, inflammation, cancer, allergy/asthma,disease and conditions of the immune system, disease and conditions ofthe central nervous system (CNS), cardiovascular disease, dermatology,and angiogenesis may be effectively treated by the administration offrom about 0.01 to 50 mg of the compound per kilogram of body weight perday, or alternatively about 0.5 mg to about 3.5 g per patient per day.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

Compounds described herein contain one or more asymmetric centers andmay thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

The invention also encompassses a pharmaceutical composition that iscomprised of a compound of Formula I in combination with apharmaceutically acceptable carrier.

Preferably the composition is comprised of a pharmaceutically acceptablecarrier and a non-toxic therapeutically effective amount of a compoundof Formula I as described above, or a pharmaceutically acceptable saltthereof

Moreover, within this preferred embodiment, the invention encompasses apharmaceutical composition for the treatment of disease by inhibitingtyrosine kinase enzymes, resulting in cell proliferation, growth,differentiation, metabolism, cell cycle events, apoptosis, motility,transcription, phosphorylation, translation and other signalingprocesses, comprising a pharmaceutically acceptable carrier and anon-toxic therapeutically effective amount of compound of formula I asdescribed above (or a pharmaceutically acceptable salt thereof).

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium slats. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N′,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric and tartaric acids.

The pharmaceutical compositions of the present invention comprise acompound represented by formula I, or a pharmaceutically acceptable saltthereof, as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In practice, the compounds represented by Formula I, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. E.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion, or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compound represented byFormula I, or a pharmaceutically acceptable salt thereof, may also beadministered by controlled release means and/or delivery devices. Thecompositions may be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula I. The compounds of Formula I, orpharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents, and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.05 mg to about 5 g of the activeingredient and each cachet or capsule preferably containing from about0.05 mg to about 5 g of the active ingredient.

For example, a formulation intended for the oral administration tohumans may contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical sue such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or a pharmaceutically acceptable saltthereof, via conventional processing methods. As an example, a cream orointment is prepared by admixing hydrophilic material and water,together with about 5 wt % to about 10 wt % of the compound, to producea cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

Generally, dosage levels on the order of from about 0.01 mg/kg to about150 mg/kg of body weight per day are useful in the treatment of theabove-indicated conditions, or alternatively about 0.5 mg to about 7 gper patient per day. For example, inflammation, cancer, allergy/asthma,disease and conditions of the immune system, disease and conditions ofthe central nervous system (CNS), cardiovascular disease, dermatology,and angiogenesis may be effectively treated by the administration offrom about 0.01 to 50 mg of the compound per kilogram of body weight perday, or alternatively about 0.5 mg to about 3.5 g per patient per day.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

Biological Assays

The efficacy of the Examples of the invention, compounds of Formula I,as inhibitors of insulin-like growth factor-I receptor (IGF-1R) weredemonstrated and confirmed by a number of pharmacological in vitroassays. The following assays and their respective methods have beencarried out with the compounds according to the invention. Activitypossessed by compounds of Formula I may be demonstrated in vivo.

In vitro Tyrosine Kinase Assay

The IGF-1R inhibitory of a compound of formula I can be shown in atyrosine kinase assay using purified GST fusion protein containing thecytoplasmic kinase domain of human IGF-1R expressed in Sf9 cells. Thisassay is carried out in a final volume of 90 μL containing 1-100 nM(depending on the specific activity) in an Immulon-4 96-well plate(Thermo Labsystems) pre-coated with 1 μg/well of substrate poly-glu-tyr(4:1 ratio) in kinase buffer (50 mM Hepes, pH 7.4, 125 mM NaCl, 24 mMMgCl₂, 1 mM MnCl₂, 1% glycerol, 200 μM Na₃VO₄, and 2 mM DTT). Theenzymatic reaction was initiated by addition of ATP at a finalconcentration of 100 μM. After incubation at room temperature for 30minutes, the plates were washed with 2 mM Imidazole buffered saline with0.02% Tween-20. Then the plate was incubated with anti-phosphotyrosinemouse monoclonal antibody pY-20 conjugated with horse radish peroxidase(HRP) (Calbiochem) at 167 ng/mL diluted in phosphate buffered saline(PBS) containing 3% bovine serum albumin (BSA), 0.5% Tween-20 and 200 μMNa₃VO₄ for 2 hours at room temperature. Following 3×250 μL was the boundanti-phosphotyrosine antibody was detected by incubation with 100μl/well ABTS (Kirkegaard & Perry Labs, Inc.) for 30 minutes at roomtemperature. The reaction was stopped by the addition of 100 μl/well 1%SDS, and the phosphotyrosine dependent signal was measured by a platereader at 405/490 nm.

All Examples showed inhibition of IGF-1R. The following Examples showedefficacy and activity by inhibiting IGF-1R in the biochemical assay withIC₅₀ values less than 15 μM. Preferably the IC₅₀ value is less than 5μM. More advantageously, the IC₅₀ value is less than 1 μM. Even moreadvantageously, the IC₅₀ value is less than 200 nM.

The most preferred Examples are selective towards IGF-1R.

Cell-Based Autophosphotyrosine Assay

NIH 3T3 cells stably expressing full-length human IGF-1R were seeded at1×10⁴ cells/well in 0.1 ml Dulbecco's minimal essential medium (DMEM)supplemented with 10% fetal calf serum (FCS) per well in 96-well plates.On Day 2, the medium is replaced with starvation medium (DMEM containing0.5% FCS) for 2 hours and a compound was diluted in 100% dimethylsulfoxide (DMSO), added to the cells at six final concentrations induplicates (20, 6.6, 2.2, 0.74, 0.25 and 0.082 μM, and incubated at 37°C. for additional 2 hours. Following addition of recombinant human IGF-1(100 ng/mL) at 37° C. for 15 minutes, the media was then removed and thecells were washed once with PBS (phosphate-buffered saline), then lysedwith cold TGH buffer (1% Triton-100, 10% glycerol, 50 mM Hepes [pH 7.4])supplemented with 150 mM NaCl, 1.5 mM MgCl, 1 mM EDTA and fresh proteaseand phosphatase inhibitors [10 μg/ml leupeptin, 25 μg/ml aprotinin, 1 mMphenyl methyl sulphonyl fluoride (PMSF), and 200 μM Na₃VO₄]. Celllysates were transferred to a 96-well microlite2 plate (Corning CoStar#3922) coated with 10 ng/well of IGF-1R antibody (Calbiochem, Cat#GR31L)and incubated at 4° C. overnight. Following washing with TGH buffer, theplate was incubated with anti-phosphotyrosine mouse monoclonal antibodypY-20 conjugated with horse radish peroxidase (HRP) for 2 hours at roomtemperature. The autophosphotyrosine was then detected by addition ofSuper Signal ELISA Femto Maximum Sensitivity Substrate (Pierce) andchemiluminescence was read on a Wallac Victor² 1420 Multilabel Counter.The IC₅₀ curves of the compounds were plotted using an ExcelFit program.

All Examples showed inhibition of IGF-1R in the cell-based assay. Thefollowing Examples showed efficacy and activity by inhibiting IGF-1Rwith IC₅₀ values less than 15 μM, with selectivity over insulin receptorexpected to be in a range from 1-15 fold. Preferably the IC₅₀ value isless than 5 μM. More advantageously, the IC₅₀ value is less than 1 μM.Even more advantageously, the IC₅₀ value is less than 200 nM. Insulinreceptor autophosphotyrosine assays are performed essentially asdescribed above for IGF-1R cell-based assays, but use insulin (10 nM) asactivating ligand and an insulin receptor antibody as capture antibodywith HepG2 cells expressing endogenous human insulin receptor.

Experimental

Schemes 1-13 describe the synthesis of the compounds of this invention.Abbreviations used in this experimental description are: Me for methyl,Et for ethyl, ^(i)Pr or ^(i)Pr for isopropyl, Ph for phenyl, Bn forbenzyl, EtOH for ethanol, MeOH for methanol, i-PrOH for isopropanol, THFfor tetrahydrofuran, CH₃CN for acetonitrile, EtOAc for ethyl acetate,NaOEt for sodium ethoxide, DMAP for 4-(dimethylamino)pyridine, DCC for1,3-dicyclohexylcarbodiimide, EDC for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBt for1-hydroxybenzotriazole, HOAt for 1-hydroxy-7-azabenzotriazole, POCl₃ forphosphorous oxychloride, Pd(PPh₃)₄ (0) fortetrakis(triphenylphosphine)palladium (0), DIEA forN,N′-diisopropylethylamine, HCl for hydrochloric acid, H₂SO₄ forsulfuric acid, NaNO₂ for sodium nitrite, Na₂SO₄ for sodium sulfate, Tsfor tosyl, Ms for mesyl, TMS for trimethylsilyl, rt for roomtemperature, min for minute, h for hour, and MDP for mass directedpurification.

Accordingly, the following are compounds which are useful asintermediates in the formation of IGF-1R inhibiting examples.

The compounds of Formula I of this invention and the intermediates usedin the synthesis of the compounds of this invention were preparedaccording to the following methods.

Method A:

where Q¹ and R¹ are as defined previously for compound of Formula I.

In a typical preparation of compounds of Formula I, compound of FormulaII was reacted with phosphorous oxychloride (POCl₃), triazole, andpyridine followed by ammonia in a suitable solvent. Suitable solventsfor use in the above process included, but were not limited to, etherssuch as tetrahydrofuran (THF), glyme, and the like; alcohols such asmethanol, ethanol, isopropanol, trifluoroethanol, and the like; andchlorinated solvents such as methylene chloride (CH₂Cl₂) or chloroform(CHCl₃). If desired, mixtures of these solvents were used, however, thepreferred solvent was isopropanol. The above process was carried out attemperatures between about 0° C. and about 50° C. Preferably, thereaction was carried out at between 0° C. and about 22° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially, equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula II of Scheme I were prepared as shown below inScheme 2.

where Q¹ and R¹ are as defined previously for compound of Formula I.

In a typical preparation of a compound of Formula II, an intermediate ofFormula III was treated with phosphorous oxychloride (POCl₃) in asuitable solvent at a suitable reaction temperature. Suitable solventsfor use in the above process included, but were not limited to, etherssuch as tetrahydrofuran (THF), glyme, and the like; and chlorinatedsolvents such as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃) andacetonitrile (CH₃CN). If desired, mixtures of these solvents were used.The preferred solvent was methylene chloride. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 40° C. and about 70° C.process to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially, equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula III of Scheme 2 were prepared as shown below inScheme 3:

where Q¹ and R¹ are as defined previously for compound of Formula I.

In a typical preparation, of a compound of Formula III, a compound ofFormula IV was treated with sodium nitrite (NaNO₂), a suitable acid in asuitable solvent, and suitable reaction temperatures. Suitable acids foruse in the above process included, but were not limited to, HCl andH₂SO₄. The preferred acid was HCl. Suitable solvents for use in theabove process included, but were not limited to, dimethylformamide(DMF); alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and H₂O. If desired, mixtures of thesesolvents were used, however, the preferred solvent was EtOH. The aboveprocess was carried out at temperatures between about −20° C. and about50° C. Preferably, the reaction was carried out between 0° C. and 22° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially, equimolar amountsof reactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula IV of Scheme 3 were prepared as shown below inScheme 4:

where Q¹ and R¹ are as defined previously for compound of Formula I.

In a typical preparation, of a compound of Formula IV, a compound ofFormula V was reacted with amidrazone VI in a suitable solvent undersuitable reaction temperatures. Suitable solvents for use in the aboveprocess included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; alcoholic solvents such asmethanol, ethanol isopropanol, trifluoroethanol and the like. Ifdesired, mixtures of these solvents may be used, however the preferredsolvent was ethanol. The above process was carried out at temperaturesbetween about −78° C. and about 80° C. Preferably, the reaction wascarried out between −20° C. and 22° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially, equimolar amounts of reactants were preferablyused although higher or lower amounts were used if desired.

The compounds of Formula V of Scheme 4 were prepared as shown below inScheme 5:

where Q¹ and R¹ are as defined previously for compound of Formula I.

In a typical preparation of a compound of Formula V, a compound ofFormula VII was reacted ethyl oxalyl chloride, pyridine, and catalyticDMAP using suitable solvents under suitable reaction temperatures.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;acetonitrile (CH₃CN); chlorinated solvents such as methylene chloride(CH₂Cl₂) or chloroform (CHCl₃). If desired, mixtures of these solventswere used, however, the preferred solvent was THF. The above process maybe carried out at temperatures between about 0° C. and about 100° C.Preferably, the reaction was carried out at 70° C. The above process toproduce compounds of the present invention was preferably carried out atabout atmospheric pressure although higher or lower pressures were usedif desired. Substantially, equimolar amounts of reactants werepreferably used although higher or lower amounts were used if desired.One skilled in the art would recognize that N-acylated amino acids,compounds of Formula VII, are generally commercially available or can begenerally synthesized via treatment of the amino acid precursor with asuitable acylating agent (other suitable reaction conditions for theacylation of an amine can be found in (Larock, R. C. ComprehensiveOrganic Transformations, 2^(nd) ed.; Wiley and Sons: New York, 1999, pp1941-1949). One skilled in the art would also recognize that the aminoacid precursors are generally commercially available or can be preparedaccording to conventional methods such as the known Strecker synthesisfor amino acids (March. Advanced Organic Chemistry: Reactions,Mechanisms, and Structure, 4^(th) ed.; Wiley and Sons: New York, 1992,pp 965). One skilled in the art would recognize that either racemic orenantiomerically enriched amino acids and/or derivatives of Formula VIImay be used.

The compounds of Formula III of Scheme 2 may be prepared as shown belowin Scheme 6:

where Q¹ and R¹ are as defined previously for compound of Formula I andA¹-C═O is defined as an acyl group which is removable under suitablereaction conditions.

In a typical preparation, of a compound of Formula III, a compound ofFormula III, can be treated under suitable conditions to afford theremoval of A¹-C═O in a suitable solvent at a suitable temperature toafford compound of Formula VIII. Suitable conditions for use in theabove process include, but are not limited to, treatment of compounds ofFormula IIIa under hydrolytic conditions such as HCl in water or basicconditions such NaOH and the like in water. Suitable solvents for use inthe above process include, but were not limited to, dimethylformamide(DMF); alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; ethers such as tetrahydrofuran (THF),glyme, and the like; acetonitrile (CH₃CN); and H₂O. If desired, mixturesof these solvents were used. The above process can be carried out attemperatures between about −20° C. and about 100° C. Preferably, thereaction can be carried out between 22° C. and 80° C. The above processto produce compounds of the present invention can be preferably carriedout at about atmospheric pressure although higher or lower pressures canbe used if desired. Substantially, equimolar amounts of reactants can bepreferably used although higher or lower amounts can be used if desired.In a typical preparation, of a compound of Formula III, a compound ofFormula VIII and a suitable acylating agent (R¹CO₂H or R¹COCl) can bereacted under suitable amide coupling conditions. Suitable conditionsinclude but are not limited to treating compounds of Formula VIII andR¹CO₂H with coupling reagents such as DCC or EDC in conjunction withDMAP, HOBt, HOAt and the like or treating compounds of Formula VIII andR¹COCl with base such as DIEA and the like. In either case suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride. Ifdesired, mixtures of these solvents were used. The above process can becarried out at temperatures between about 0° C. and about 80° C. Theabove process to produce compounds of the present invention can bepreferably carried out at about atmospheric pressure although higher orlower pressures can be used if desired. Substantially, equimolar amountsof reactants can be preferably used although higher or lower amounts canbe used if desired. Additionally, other suitable reaction conditions forthe conversion of RNH₂ to R¹CONHR can be found in Larock, R. C.Comprehensive Organic Transformations, 2^(nd) ed.; Wiley and Sons: NewYork, 1999, pp 1941-1949.

Method B was also used when preparing compounds of Formula I as shownbelow in Scheme 7:

Method B:

where Q¹ and R¹ are as defined previously for compound of Formula I;A¹¹=halogen such as Cl, Br, or I; and B(OR)₂=suitable boronic acid/esterwherein each R is independently C₀₋₆alkyl or each R is independentlyC₁₋₆alkyl taken together with the respective oxygen atom to which theyare attached to form a 5-15 membered saturated or partially unsaturatedring wherein said ring is optionally substituted with 1-4 independentC₀₋₁₀alkyl substituents.

In a typical preparation of compounds of Formula I, compound of FormulaIX was reacted with a suitable boronic acid/ester (Q¹-B(OR)₂) of FormulaXVIII in a suitable solvent via typical Suzuki coupling procedures. Acompound of Formula XVIII can be commercially available or made byliterature procedures from a suitable reagent such as an aryl halide anda diborane see 2-fluoro-3-benzyloxyphenylboronic acid pinacol ester asan example. Suitable solvents for use in the above process included, butwere not limited to, water, ethers such as tetrahydrofuran (THF), glyme,and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent wasglyme/water. The above process was carried out at temperatures betweenabout −78° C. and about 120° C. Preferably, the reaction was carried outbetween 80° C and about 100° C. The above process to produce compoundsof the present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Substantially, equimolar amounts of reactants were preferably usedalthough higher or lower amounts were used if desired. One skilled inthe art will appreciate that alternative methods may be applicable forpreparing compounds of Formula I from IX. For example, compound ofFormula IX could be reacted with a suitable organotin reagent Q¹-SnBu₃or the like in a suitable solvent via typical Stille couplingprocedures.

The compounds of Formula IX of Scheme 7 were prepared as shown below inScheme 8.

where R¹ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula IX, compound of FormulaX was reacted with phosphorus oxychloride (POCl₃) and triazole, andpyridine followed by ammonia (NH₃) in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was isopropanol. The above process wascarried out at temperatures between about −20° C. and about 50° C.Preferably, the reaction was carried out between 0° C. and about 25° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially, equimolar amountsof reactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula X of Scheme 8 were prepared as shown below inScheme 9.

where R¹ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of a compound of Formula X, compound XII wasconverted to compound of Formula XI. Compound of Formula XII was treatedwith phosphorus oxychloride (POCl₃) in a suitable solvent at a suitablereaction temperature. Suitable solvents for use in the above processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like, chlorinated solvents such as methylene chloride(CH₂Cl₂) or chloroform (CHCl₃), and acetonitrile (CH₃CN). If desired,mixtures of these solvents were used. The preferred solvent wasacetonitrile. The above process was carried out at temperatures betweenabout −78° C. and about 120° C. Preferably, the reaction was carried outbetween 40° C. and about 95° C. The above process to produce compoundsof the present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Compounds for Formula X was prepared by reacting compound of Formula XIwith a suitable halogenating agent. Suitable halogenating agentsincluded, but were not limited to, Br₂, I₂, Cl₂, N-chlorosuccinimide,N-bromosuccinimide, or N-iodosuccinimide. The preferred halogenatingagent was N-iodosuccinimide. Suitable solvents for use in the aboveprocess included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; alcohols such as methanol,ethanol, isopropanol, trifluoroethanol, and the like; and chlorinatedsolvents such as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). Ifdesired, mixtures of these solvents were used, however, the preferredsolvent was DMF. The above process was carried out at temperaturesbetween about −78° C. and about 120° C. Preferably, the reaction wascarried out between 40° C. and about 75° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially, equimolar amounts of reactants were preferablyused although higher or lower amounts were used if desired.

The compounds of Formula XII of Scheme 9 were prepared as shown below inScheme 10:

where R¹ is as defined previously for compound of Formula I and A¹¹¹=OH,alkoxy, or a leaving group such as chloro or imidazole.

In a typical preparation, of a compound of Formula XII, a compound ofFormula XIII and compound of Formula XIV were reacted under suitableamide coupling conditions. Suitable conditions include but are notlimited to treating compounds of Formula XIII and XIV (when A¹¹¹=OH)with coupling reagents such as DCC or EDC in conjunction with DMAP,HOBt, HOAt and the like. Suitable solvents for use in the above processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; halogenated solvents such as chloroform or methylenechloride. If desired, mixtures of these solvents were used, however thepreferred solvent was methylene chloride. The above process was carriedout at temperatures between about 0° C. and about 80° C. Preferably, thereaction was carried out at about 22° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially, equimolar amounts of reactants were preferablyused although higher or lower amounts were used if desired.Alternatively, compounds of Formula XIII and XIV (where A¹¹¹=Cl, Br)were reacted with bases such as triethylamine (TEA) orN,N′-diisopropylethylamine and the like in conjunction with DMAP and thelike. Suitable solvents for use in this process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;pyridine; halogenated solvents such as chloroform or methylene chloride.If desired, mixtures of these solvents were used, however the preferredsolvent was DMF. The above process was carried out at temperaturesbetween about −20° C. and about 40° C. Preferably, the reaction wascarried out between 0° C. and 25° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially, equimolar amounts of compounds of Formula XIIIand XIV (where A¹¹¹=Cl, Br) and base and substochiometric amounts ofDMAP were preferably used although higher or lower amounts were used ifdesired. Additionally, other suitable reaction conditions for theconversion of an amine (compound of Formula XIII) to an amide (compoundof Formula XII) can be found in Larock, R. C. Comprehensive OrganicTransformations, 2^(nd) ed.; Wiley and Sons: New York, 1999, pp1941-1949.

The compounds of Formula XIII of Scheme 10 were prepared as shown belowin Scheme 11:

In a typical preparation, of a compound of Formula XIII, a compound ofFormula XV is reacted under suitable reaction conditions in a suitablesolvent. Suitable conditions include treatment of compound of Formula XVwith hydrazine or alkyl hydrazine derivatives in a suitable solvent.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride; alcoholsolvents such as methanol and ethanol. If desired, mixtures of thesesolvents may be used, however the preferred solvents were ethanol andmethylene chloride. The above process was carried out at temperaturesbetween about 0° C. and about 80° C. Preferably, the reaction wascarried out at about 22° C. The above process to produce compounds ofthe present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Substantially, equimolar amounts of reactants were preferably usedalthough higher or lower amounts were used if desired.

The compounds of Formula XV of Scheme 11 were prepared as shown below inScheme 12:

In a typical preparation of a compound of Formula XV, a compound ofFormula XVI was reacted with Raney Nickel in a suitable solvent.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile(CH₃CN); alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; chlorinated solvents such as methylenechloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixtures of thesesolvents were used, however, the preferred solvent was ethanol. Theabove process may be carried out at temperatures between about rt andabout 100° C. Preferably, the reaction was carried out at about 80° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially, equimolar amountsof reactants were preferably used although higher or lower amounts wereused if desired. Additionally a compound of Formula XV can be preparedby reacting a compound of Formula XVI with a suitable oxidizing agent ina suitable solvent. A suitable oxidizing agent includes, but is notlimited to hydrogen peroxide (H₂O₂), 3-chloroperoxybenzoic acid (mCPBA)and the like. Suitable solvents for use in the above process included,but were not limited to, ethers such as THF, glyme, and the like; DMF;DMSO; CH₃CN; and dimethylacetamide (DMA); chlorinated solvents such asCH₂Cl₂ or CHCl₃. If desired, mixtures of these solvents were used,however, the preferred solvent was DMA. The above process may be carriedout at temperatures between about 0° C. and 100° C. Preferably, thereaction was carried out at about rt to 70° C. The above process toproduce compounds of the present invention was preferably carried out atabout atmospheric pressure although higher or lower pressures were usedif desired. Substantially, equimolar amounts of reactants werepreferably used although higher or lower amounts were used if desired.

The compounds of Formula XVI of Scheme 12 were prepared as shown belowin Scheme 13:

In a typical preparation of a compound of Formula XVI, a compound ofFormula XVII was reacted with thiosemicarbazide and a suitable base in asuitable solvent. Suitable bases include, but were not limited totriethylamine, N,N′-diisopropylethylamine (DIEA) and the like. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethylacetamide (DMA); dimethyl sulfoxide(DMSO); acetonitrile (CH₃CN); alcohols such as methanol (MeOH), ethanol(EtOH, isopropanol (i-PrOH), trifluoroethanol, and the like; chlorinatedsolvents such as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). Ifdesired, mixtures of these solvents were used, however, the preferredsolvent was ethanol. The above process may be carried out attemperatures between about rt and about 100° C. Preferably, the reactionwas carried out between about 40° C. and 80° C. The above process toproduce compounds of the present invention was preferably carried out atabout atmospheric pressure although higher or lower pressures were usedif desired. Substantially, equimolar amounts of reactants werepreferably used although higher or lower amounts were used if desired.Compound of Formula XVII can be prepared according to literatureprocedures Knutsen, Lars J. S. et. al., J. Chem. Soc. Perkin Trans 1:Organic and Bio-Organic Chemistry (1972-1999), 1984, 229-238.

It would be appreciated by those skilled in the art that in somesituations, a substituent that is identical or has the same reactivityto a functional group which has been modified in one of the aboveprocesses, will have to undergo protection followed by deprotection toafford the desired product and avoid undesired side reactions.Alternatively, another of the processes described within this inventionmay be employed in order to avoid competing functional groups. Examplesof suitable protecting groups and methods for their addition and removalmay be found in the following reference: “Protective Groups in OrganicSyntheses”, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, 1989.

Throughout Scheme 1-13, R¹ can be optionally substituted with a suitablefunctional group that can be further modified. For example, R¹ incompound of Formula I, can equal cyclohexyl-4-CO₂Me. The 4-CO₂Mefunctional group can be subsequently converted into CH₂OH via treatmentwith a suitable reducing agent such as lithium aluminum hydride. Thealcohol, CH₂OH, can be further converted into a suitable leaving groupsuch as a tosylate (CH₂OTs) or mesylate (CH₂OMs) followed bydisplacement with a suitable nucleophile such as dimethylamine to affordCH₂N(CH₃)₂.

The following examples are intended to illustrate and not to limit thescope of the present invention.

General Experimental Information:

All melting points were determined with a Mel-Temp II apparatus and areuncorrected. Commercially available anhydrous solvents and HPLC-gradesolvents were used without further purification.

¹H NMR and ¹³C NMR spectra were recorded with Varian or Brukerinstruments (400 MHz for ¹H, 100.6 MHz for ¹³C) at ambient temperaturewith TMS or the residual solvent peak as internal standards. The linepositions or multiplets are given in ppm (δ) and the coupling constants(J) are given as absolute values in Hertz, while the multiplicities in¹H NMR spectra are abbreviated as follows: s (singlet), d (doublet), t(triplet), q (quartet), quint (quintet), m (multiplet), m_(c) (centeredmultiplet), br (broadened), AA′BB′. The signal multiplicities in ¹³C NMRspectra were determined using the DEPT135 pulse sequence and areabbreviated as follows: +(CH or CH₃), −(CH₂), C_(quart) (C). LC/MSanalysis was performed using a Gilson 215 autosampler and Gilson 819autoinjector attached to a Hewlett Packard HP1100 and a MicromassZQ massspectrometer, or a Hewlett Packard HP1050 and a Micromass Platform IImass spectrometer. Both setups used XTERRA MS C18 5 μ 4.6×50 mm columnswith detection at 254 nm and electrospray ionization in positive mode.For mass-directed purification (MDP), a Waters/Micromass system wasused.

The tables below list the mobile phase gradients (solvent A:acetonitrile; solvent B: 0.01% formic acid in HPLC water) and flow ratesfor the analytical HPLC programs.

Polar_(—)5 Min

Flow Rate Flow Rate (mL/min) (mL/min) Time A % B % MicromassZQ PlatformII 0.00 5 95 1.3 1.3 3.00 90 10 1.3 1.3 3.50 90 10 1.3 1.3 4.00 5 95 1.31.3 5.00 5 95 1.3 1.3Nonpolar_(—)5 min

Flow Rate Flow Rate (mL/min) (mL/min) Time A % B % MicromassZQ PlatformII 0.00 25 75 1.3 1.3 3.00 99 1 1.3 1.3 3.50 99 1 1.3 1.3 4.00 25 75 1.31.3 5.00 25 75 1.3 1.3

EXAMPLE 15-(3-benzyloxy-phenyl)-7-cyclobutyl-imidazo[5,1-f][1,2,4]triazin-4-ylamine(Compound of Formula I where R¹=cyclobutyl and Q¹=Ph-(3-OBn)) wasprepared as follows:

To a solution of 1,2,4-triazole (167 mg, 2.417 mmol) in anhydrouspyridine (1.5 mL) was added phosphorous oxychloride (POCl₃) (75 μL,0.806 mmol) and stirred at rt for 15 min. To this mixture was addeddropwise a solution of5-(3-benzyloxy-phenyl)-7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one(100 mg, 0.269 mmol) in anhydrous pyridine (2.5 mL) over a 3.5 minperiod and stirred at rt for an additional 3 h. The reaction was cooledto 0° C. and quenched with 2M NH₃ in i-PrOH (10 mL ) and stirred for anadditional 30 min at rt. The mixture was filtered through a frittedfunnel and the filtrate was concentrated in vacuo, partitioned betweenCHCl₃ and H₂O and separated. The aqueous layer was re-extracted withCHCl₃ (3×) and the combined CHCl₃ fractions were washed with brine (1×),dried over Na₂SO₄, filtered and concentrated in vacuo and the crudematerial was chromatographed on silica gel [eluting with 2% MEOH inCHCl₃] resulting in a dark brown oil which was crystallized fromEtOAc/hexanes to obtain the title compound as a light tan solid. ¹H NMR(CDCl₃, 400 MHz) δ 1.95-2.08 (m, 1H), 2.09-2.22 (m, 1H), 2.39-2.50 (m,2H), 2.59-2.72 (m, 2H), 4.14 (quint, J=8.4 Hz, 1H), 5.16 (s, 2H), 5.57(brs, 2H), 7.02-7.09 (m, 1H), 7.22-7.28 (m, 3H), 7.31-7.50 (m, 5H), 7.85(s, 1H); MS (ES+): m/z 372.1 (100) [MH⁺]; HPLC: t_(R)=3.05 min(MicromassZQ, nonpolar_(—)5 min).

5-(3-benzyloxy-phenyl)-7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one(Compound of Formula II where R¹=cyclobutyl and Q¹=Ph-(3-OBn)) wasprepared as follows:

A solution of cyclobutanecarboxylic acid[(3-benzyloxy-phenyl)-(5-oxo-4,5-dihydro-[1,2,4]triazin-6-yl)-methyl]-amide(216 mg, 0.553 mmol) in POCl₃ (5 mL) was heated to 55° C. in an oil bathfor 3 h. The reaction mixture was concentrated in vacuo and cooled to 0°C. and charged with 2M NH₃ in i-PrOH until slightly basic. The solutionwas concentrated in vacuo and the reaction mixture was partitionedbetween EtOAc and H₂O and separated. The aqueous layer was re-extractedwith EtOAc (3×) and the combined EtOAc fractions were dried over Na₂SO₄,filtered and concentrated in vacuo to obtain the title compound as anoff-white foam solid with no further purification. ¹H NMR (CDCl₃, 400MHz) δ 1.98-2.07 (m, 1H), 2.08-2.21 (m, 1H), 2.36-2.48 (m, 2H),2.62-2.77 (m, 2H), 4.09 (quint, J=8.8 Hz, 1H), 5.13 (s, 2H), 6.98 (dd,J=2.0, 7.2 Hz, 1H), 7.27-7.7.40 (m, 4H), 7.42-7.49 (m, 3H), 7.88 (d,J=8.0 Hz, 1H), 7.99 (brs, 1H); MS(ES+): m/z 373.1 (100) [MH⁺]; HPLC:t_(R)=3.25 min (MicromassZQ, nonpolar_(—)5 min).

Cyclobutanecarboxylic acid[(3-benzyloxy-phenyl)-(5-oxo-4,5-dihydro-[1,2,4]triazin-6-yl)-methyl]-amide(Compound of Formula III where R¹=cyclobutyl and Q¹=Ph-(3-OBn)) wasprepared as follows:

To a solution of cyclobutanecarboxylic acid[(4-amino-5-oxo-4,5-dihydro-[1,2,4]triazin-6-yl)-(3-benzyloxy-phenyl)-methyl]-amide(315 mg, 0.777 mmol) and concentrated HCl (344 μL) in anhydrous EtOH (16mL) was dropwise added a solution of sodium nitrite (120 mg, 1.72 mmol)in H₂O (4 mL) at 0° C. and stirred for 30 min and warmed to rt for anadditional 1.5 h. The reaction mixture was concentrated in vacuo and thecrude material was chromatographed on silica gel [eluting with 3% MeOHin CHCl₃] to obtain the title compound as an off-white foam solid. ¹HNMR (CDCl₃, 400 MHz) δ 1.78-1.93 (m, 1H), 1.93-2.04 (m, 1H), 2.12-2.2.36(m, 4H), 3.13 (quint, J=8.4 Hz, 1H), 4.97 (s, 2H), 6.35 (d, J=8.8 Hz,1H), 6.85 (dd, J=2.4, 8.4 Hz, 1H), 6.96-7.05 (m, 2H), 7.20 (t, J=8.0 Hz,1H), 7.27-7.41 (m, 4H), 7.61 (brs, 1H), 8.46 (s, 1H); MS (ES+): m/z391.04 (100) [MH⁺]; HPLC: t_(R)=2.87 min (MicromassZQ, polar_(—)5 min).

Cyclobutanecarboxylic acid[(4-amino-5-oxo-4,5-dihydro-[1,2,4]triazin-6-yl)-(3-benzyloxy-phenyl)-methyl]-amide(Compound of Formula IV where R¹=cyclobutyl and Q¹=Ph-(3-OBn)) wasprepared as follows:

A solution of formamidine HCl (163 mg, 2.02 mmol) in anhydrous EtOH (8mL) was cooled to 0° C. and was charged with a 1M solution of hydrazinein THF (4.05 mL, 4.05 mmol) over a 4 min period and stirred at rt for 8min. The reaction mixture was cooled to −20° C. and charged with asolution of3-(3-benzyloxy-phenyl)-3-(cyclobutanecarbonyl-amino)-2-oxo-propionicacid ethyl ester (800 mg, 2.02 mmol) in anhydrous EtOH (16 mL) over a 15min period and stirred at −20° C. for an additional 15 min and allowedto warm to rt for 4 h. The reaction mixture was concentrated in vacuoand the crude material was chromatographed on silica gel [eluting with3% MeOH in CHCl₃], yielding the title compound as a light yellow foamsolid. ¹H NMR (CDCl₃, 400 MHz) δ 1.78-2.04 (m, 2H), 2.08-2.34 (m, 4H),3.07 (quint, J=8.4 Hz, 1H), 4.92 (s, 2H), 5.03 (s, 1H), 6.49 (d, J=8.0Hz, 1H), 6.84-6.92 (m, 1H), 6.95-7.10 (m, 3H), 7.23 (t, J=8.0 Hz, 1H),7.28-7.46 (m, 4H), 8.42 (s, 1H); MS (ES+): m/z 406.08 (100) [MH⁺]; HPLC:t_(R)=3.04 min (MicromassZQ, polar_(—)5 min).

3-(3-benzyloxy-phenyl)-3-(cyclobutanecarbonyl-amino)-2-oxo-propionicacid ethyl ester (Compound of Formula V where R¹=cyclobutyl andQ¹=Ph-(3-OBn)) was prepared as follows:

A slurry of (3-benzyloxy-phenyl)-(cyclobutanecarbonyl-amino)-acetic acid(4.77 g, 14.1 mmol), pyridine (3.4 mL, 42.2 mmol) and DMAP (cat.) inanhydrous THF (26 mL) was charged dropwise with chloro-oxo-acetic acidethyl ester (3.13 mL, 28.1 mmol) and heated to reflux for 1.5 h. Thewhite precipitate was filtered through a fritted glass Buchner funnelinto a flask containing H₂O and EtOAc and the aqueous phase wasseparated from the organic phase. The aqueous was washed with EtOAc (3×)and the combined EtOAc layers were washed with brine (1×), dried overNa₂SO₄, filtered and concentrated in vacuo resulting in a yellow/orangeoil. The oil was dissolved in anhydrous EtOH (28 mL) and a solution of21 wt % of sodium ethoxide (NaOEt) in EtOH (2.0 mnL) was added at 0° C.and warmed to rt. The reaction mixture was concentrated in vacuo and thecrude material was chromatographed on silica gel [eluting with 2% EtOAcin CHCl₃], yielding the title compound as a pale yellow oil. ¹H NMR(CDCl₃, 400 MHz) δ 1.26 (t, J=7.2 Hz, 3H), 1.80-2.04 (m, 2H), 2.09 (m,4H), 3.06 (quint, J=8.4 Hz, 1H) 4.17-4.30 (m, 2H), 5.04 (s, 2H),6.18-6.32 (m, 2H), 6.86-7.00 (m, 3H), 7.22-7.48 (m, 5H); MS (ES+): m/z396.03 (100) [MH⁺]; HPLC: t_(R)=3.09 min (MicromassZQ, nonpolar_(—)5min).

EXAMPLE 25-(3-benzyloxy-2-fluoro-phenyl)-7-cyclobutyl-imidazo[5,1-f][1,2,4]triazin-4-ylamine(compound of Formula I where R¹=cyclobutyl and Q¹=2-fluoro-Ph-(3-OBn))was prepared as follows:

A flask was charged with7-cyclobutyl-5-iodo-imidazo[5,1-f][1,2,4]triazin-4-ylamine (30 mg, 0.095mmol), 2-(3-benzyloxy-2-fluoro-phenyl)-4,4,5,5- tetramethyl[1,3,2]dioxaborolane (62.5 mg, 0.158 mmol), and sodium carbonate (30 mg,0.286 mmol) and was evacuated and charged with N₂ (3×). This mixture wascharged with tetrakis(triphenylphosphine palladium (0) (Pd(PPh₃)₄ (0))(36 mg, 0.0318 mmol) and the tube was re-evacuated and charged with N₂(2×). This mixture was then charged with a previously degassed solventDME/H₂O (5:1)(3 mL) and heated to 75° C. for 16 h. The reaction mixturewas concentrated in vacuo and dissolved in MeOH/CH₃CN (1:1) (5 mL),filtered though a 0.45 μM fritted autovial and submitted for massdirected purification (MDP) resulting in the title compound as a whitesolid.

¹H NMR (DMSO-d₆, 400 MHz) δ 1.86-1.98 (m, 1H), 2.00-2.14 (m, 1H),2.30-2.41 (m, 2H), 2.41-2.48 (m, 2H), 3.98-4.09 (m, 1H), 5.24 (s, 2H),6.27 (brs, 1H), 7.05-7.12 (m, 1H), 7.22 (t, J=8.27 Hz, 1H), 7.29-7.52(m, 6H), 7.88 (s, 1H), 8.15 (brs, 1H); MS (ES+): m/z 389.98 (100),[MH⁺], HPLC: t_(R)=3.44 min (MicromassZQ, polar_(—)5 min).

7-cyclobutyl-5-iodo-imidazo[5,1-f][1,2,4]triazin-4-ylamine (Compound ofFormula IX where R¹=cyclobutyl and A¹¹=iodine) was prepared as follows:

To a solution of 1,2,4-triazole (1.28 g, 18.59 mmol) in anhydrouspyridine (10 mL) was added phosphorus oxychloride (POCl₃) (0.578 mL,6.20 mmol) and stirred at rt for 15 min. This mixture was dropwisecharged (3.5 min) with a solution of 7-cyclobutyl-5-iodo-3Himidazo[5,1f][1,2,4]triazin-4-one (0.653 mg, 2.07 mmol) in anhydrouspyridine (14 mL) and stirred for 1.5 h. The reaction mixture was cooledto 0° C. quenched with 2M NH₃ in isopropanol (i-PrOH) until basic thenallowed to reach rt and stirred for an additional 2 h. The reactionmixture was filtered through a fritted Buchner funnel and washed withCH₂Cl₂. The filtrate was concentrated in vacuo and purified bychromatography on silica gel [eluting with 30% EtOAc in CH₂Cl₂]resulting in the title compound as an off-white solid; ¹H NMR (CDCl₃,400 MHz) δ 1.93-2.04 (m, 1H), 2.05-2.18 (m, 1H), 2.35-2.45 (m, 2H),2.49-2.62 (m, 2H), 4.00-4.12 (m, 1H), 7.82 (s, 1H); MS (ES+): m/z 316.08(100) [MH⁺], HPLC: t_(R)=2.59 min (MicromassZQ, polar_(—)5 min).

7-cyclobutyl-5-iodo-3H-imidazo[5,1-f][1,2,4]triazin-4-one (compound ofFormula X where R¹=cyclobutyl and A¹¹=iodine) was prepared as follows:

A solution of 7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (789mg, 4.15 mmol) and N-iodosuccinimide (933 mg, 4.15 mmol) in anhydrousDMF (40 mL) was stirred overnight at rt. An additional 4 equiv ofN-iodosuccinimide was added and reaction was heated to 55° C. for 6 h.The reaction mixture was concentrated in vacuo and partitioned betweenCH₂Cl₂ and H₂O and separated. The aqueous layer was washed with CH₂Cl₂(3×) and the combined organic fractions were washed with 1M sodiumthiosulfate (Na₂S₂O₃) (1×), brine (1×), dried over sodium sulfate(Na₂SO₄), filtered, and concentrated vacuo. The solid was trituratedwith 20% EtOAc in DCM and filtered through a fritted Buchner funnelresulting in the title compound as an off-white solid; ¹H NMR (DMSO-d₆,400 MHz) δ 1.84-1.96 (m, 1H), 1.98-2.13 (m, 1H), 2.25-2.43 (m, 4H),3.84-3.96 (m, 1H), 7.87 (s, 1H); MS (ES+): m/z 317.02 (100) [MH⁺], HPLC:t_(R)=2.62 min (MicromassZQ, polar_(—)5 min).

7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (Compound of FormulaXI where R¹=cyclobutyl) was prepared as follows:

A solution of cyclobutanecarboxylic acid(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)-amide (1.33 g, 6.39 mmol)in phosphorus oxychloride (POCl₃) (10 mL) was heated to 55° C. Thereaction was heated for 2 h then concentrated in vacuo and the crude oilwas cooled to 0° C. in an ice-bath and quenched with 2 M NH₃ inispropanol (i-PrOH) until slightly basic. This crude reaction mixturewas concentrated in vacuo and was partitioned between CH₂Cl₂ and H₂O andseparated. The aqueous layer was extracted with CH₂Cl₂ (3×) and thecombined organic fractions were dried over sodium sulfate (Na₂SO₄),filtered and concentrated in vacuo. The crude material was purified bychromatography on silica gel [eluting with 5% MeOH in CH₂Cl₂], resultingin the title compound as an off-white solid; ¹H NMR (DMSO-d₆, 400 MHz) δ1.86-1.96 (m, 1H), 2.00-2.13 (m, 1H); 2.26-2.46 (m, 4H); 3.87-4.00 (m,1H); 7.71 (s, 1H); 7.87 (d, J=3.6 Hz, 1H); 11.7 (brs, 1H); MS (ES+): m/z191.27 (100) [MH⁺], HPLC: t_(R)=2.06 min (MicromassZQ, polar_(—)5 min).

Cyclobutanecarboxylic acid(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)-amide (compound of FormulaXII where R¹=cyclobutyl) was prepared as follows:

To a solution of 6-aminomethyl-4H-[1,2,4]triazin-5-one (500 mg, 3.96mmol) and N,N′-diisopropylethylamine (DIEA) (0.829 mL, 4.76 mmol) inanhydrous N,N′-dimethylforamide (DMF) (20 mL) and anhydrous pyridine (2mL) was dropwise charged with cyclobutanecarbonyl chloride (0.451 mL,3.96 mmol) at 0° C. then warmed to rt and stirred for an additional 1.5h. The reaction mixture was quenched with H₂O (2 mL), concentrated invacuo, and purified by chromatography on silica gel [eluting with 5%MeOH in CH₂Cl₂ (200 mL)→10% MeOH in CH₂Cl₂ (800 mL)], affording thetitle compound; ¹H NMR (DMSO-d₆, 400 MHz) δ 1.7-1.82 (m, 1H), 1.70-1.92(m, 1H); 1.97-2.07 (m, 2H); 2.07-2.19 (m, 2H); 3.55-3.67 (m, 1H); 4.19(d, 2H); 7.97 (brt, J=5.6 Hz, 1H); 8.67 (s, 1H); MS (ES+): m/z 209.25(100) [MH⁺], HPLC: t_(R)=1.56 min (MicromassZQ, polar_(—)5 min).

6-aminomethyl-4H-[1,2,4]triazin-5-one (Compound of Formula XIII) wasprepared as follows:

A slurry of2-(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)-isoindole-1,3-dione (4g, 15.6 mmol) in CH₂Cl₂/EtOH (1:1) (150 mL ) was charged with anhydroushydrazine (1.23 mL, 39.0 mmol) and stirred at rt for 18 h. The reactionmixture was concentrated in vacuo and the off-white solid was trituratedwith warm CHCl₃ and filtered through a fritted funnel. The solid wasthen triturated with hot methanol (MeOH) and filtered through a frittedfunnel resulting in an off-white solid. The material was triturated asecond time as before and dried overnight resulting in the titlecompound as a white solid, which was taken on to the next step withoutfurther purification; ¹H NMR (DMSO-d₆, 400 MHz) δ 3.88(s, 2H), 8.31 (2,1H); MS (ES+): m/z 127.07 (100) [MH⁺], HPLC: t_(R)=0.34 min(MicromassZQ, polar_(—)5 min).

2-(5oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)-isoindole-1,3-dione(Compound of Formula XV) was prepared as follows:

A slurry of2-(5-oxo-3-thioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylmethyl)-isoindole-1,3-dione(1.0 g, 3.47 mmol) in EtOH (40 mL) was charged with excess Raney Nickel(3 spatula) and heated to reflux for 2 h. The reaction mixture wasfiltered hot through a small pad of celite and washed with a hot mixtureof EtOH/THF (1:1) (100 mL) and the filtrate was concentrated in vacuoresulting in the title compound as an off-white solid; ¹H NMR (DMSO-d₆,400 MHz) δ 4.75 (s, 2H), 7.84-7.98 (m, 4H), 8.66 (s, 1H); MS (ES+): m/z257.22 (100) [MH⁺], HPLC: t_(R)=2.08 min (MicromassZQ, polar_(—)5 min).

2-(5-oxo-3-thioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylmethyl)-indan-1,3-dione(Compound of Formula XVI) was prepared as follows:

A slurry of 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-oxo-propionic acidethyl ester (20 g, 76.6 mmol) in anhydrous EtOH (300 mL) was chargedwith thiosemicarbazide (6.98 g, 76.6 mmol) in one portion and heated to80° C. for 2 h. The reaction mixture was charged withN,N′-diisopropylethylamine (DIEA) (26.7 mL, 76.56 mmol) and heated to40° C. for 6 h then stirred at rt for an additional 10 h. The reactionmixture was concentrated in vacuo and solid was triturated with hotEtOH/EtOAc filtered and washed with EtOAc. The solid was dried overnightin a vacuum oven (40° C.) resulting in the title compound as anoff-white solid; ¹H NMR (DMSO-d₆, 400 MHz) δ 4.68 (s, 2H), 7.85-7.95 (m,4H); MS (ES+): m/z 289.2 (100) [MH⁺], HPLC: t_(R)=2.50 min (MicromassZQ,polar_(—)5 min).

2-fluoro-3-benzyloxyphenylboronic acid pinacol ester (Compound ofFormula XVIII where Q¹=2-fluoro-Ph) was prepared as follows:

A mixture of 1-(benzyloxy)-3-chloro-2-fluorobenzene (7.1 g, 30.0 mmol),bis(pinacol)diboron (9.142 g, 36.0 mmol), Palladium(II) acetate (0.337g, 1.50 mmol), potassium acetate (7.711 g, 78.6 mmol) and1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (0.9 g, 2.12 mmol) inTHF was refluxed under nitrogen overnight. The mixture was diluted withethyl acetate (100 mL) and brine (30 mL), then filtered through celite.The yellow liquid was then separated and the organic layer was driedover anhydrous sodium sulfate. Concentration of the liquid under reducedpressure gave a grey solid, which was recrystallized from hexanes togive the title compound as a white powder. ¹H NMR (CDCl3, 400 MHz) δ1.37(s, 12 Hs), 5.18(s, 2H), 7.04-7.18(m, 2Hs), 7.27-7.47(m, 6H).

1-(benzyloxy)-3-chloro-2-fluorobenzene

A mixture of 3-chloro-2-fluorophenol (1.5 g, 10.2 mmol), benzyl bromide(1.71 g, 10.0 mmol) and sodium carbonate (1.10 g, 10.38 mmol) in 20 mLethylene glycol dimethyl ether and 10 mL H₂O was stirred at rt for 36 h.The reaction mixture was charged with 20 mL 1N KOH and 50 mL diethylether. The organic layer was separated, washed with brine, dried oversodium sulfate, and concentrated in vacuo to afford the title compoundas a white solid which was used without further purification. ¹H NMR(CDCl₃, 400 MHz) δ 5.16 (s, 2Hs) 6.86-7.03 (m, 3Hs) 7.31-7.48 (m, 5Hs).

1. A compound represented by Formula I:

or a pharmaceuticaly acceptable salt thereof, wherein: Q¹ is phenylsubstituted by —(X¹)₀₋₁—(Y¹)₀₋₁—R⁴ wherein X¹ is 3-(O)—, 4-(O)—,3-(NH)—, or 4-(NH)—; and Y¹ is —CH₂— or —(SO₂)—; R⁴ is C₀₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl, heteroaryl, cycloC₃₋₁₀alkyl,heterocyclyl, cycloC₃₋₁₀alkenyl, or heterocycloalkenyl, any of which isoptionaly substituted by one or more independent G⁴¹ substituents; R¹ isC₀₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, heterocyclyl, or heterobicycloC₅₋₁₀alkyl, any ofwhich is optionaly substituted by one or more independent G^(1l)substituents; each G¹¹ is independently —OR²¹, —NR²¹R³¹, —CO₂R²¹,—C(O)R²¹, —CONR²¹R³¹, —NR²¹C(═O)R³¹, —NR²¹C(═O)OR³¹,—NR²¹C(═O)NR³¹R^(21a), —NR²¹S(O)_(j3)R³¹, —OC(═O)OR²¹, —OC(═O)NR²¹R³¹,C₀₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, heterocyclyl-C₀₋₁₀alkyl,or heterocyclyl-C₂₋₁₀alkenyl, any of which is optionaly substituted withone or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R²²²¹a)_(j3a), —C(O)R²²²¹, —CO₂R^(2221, —CONR) ²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j3a)R²²²¹, —SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹,—NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹,—C(═S)OR²²²¹, —C(═O)SR²²²¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a),—NR²²²¹C(═NR³³³¹)OR^(2221a), —NR²²²¹C(═NR³³³¹)SR^(2221a), —OC(═O)OR²²²¹, —OC(═O )NR²²²¹R³³³¹, —OC(═O )SR²²²¹, —SC(═O )OR²²²¹, or —SC(═O)NR²²²¹R³³³¹; each G⁴¹ is independently halo, oxo, —CF₃, —OCF₃, —OR²,—NR²R³(R^(2a))_(j1), —C(O)R², —CO₂R², —CONR²R³, —NO₂, —CN, —S(O)_(j1)R²,—SO₂NR²R³, —NR²C(═O)R³, —NR²C(═O)O R³, —NR²C(═O )NR³R^(2a),—NR²S(O)_(j1)R³, —C(═S)O R², —C(═O )SR², —NR²C(═NR³)NR^(2a)R^(3a),—NR²C(═NR³)OR^(2a), —NR²C(═NR³)SR^(2a), —OC(═O)O R², —OC(═O)NR²R³,—OC(═O )SR², —SC(═O)OR², —SC(═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionaly substituted withone or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R^(222a))_(j1a), —C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —NO₂,—CN, —S(O)_(j1a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³,—NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j1a)R³³³, —C(═S)OR²²², —C(═)SR²²²,—NR²²²C(═NR³³³)NR^(222a)R^(333a), —NR²²²C(═NR³³³)OR^(222a), —NR²²²C(═CNR³³³)SR^(222a), —OC(═O )OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²²,—SC(═O)OR²²², or —SC(═O)NR²²²R³³³ substituents; or G⁴¹ can beindependently aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl- C₂₋₁₀alkynyl, anyof which is optionaly substituted with one or more independent halo,—CF₃, —OCF₃, —OR²²², —NR²²²R³³³(R^(222a))_(j2a), —C(O)R²²², —CO₂R²²²,—CONR²²²R³³³, —NO₂, —CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, —NR²²²C(═O)R³³³, —NR²²²C(═O)OR³³³, —NR²²²C(═O)NR³³³R^(222a), —NR²²²S(O)_(j2a)R³³³,—C(═S)OR²²², —C(═O )SR²²²,—NR²²²C(═NR³³³)NR^(222a)R^(333a),—NR²²²C(═NR³³³)OR^(222a), —NR²²²C(═NR³³³)SR^(222a), —OC(═O)OR²²², —OC(═O)NR²²²R³³³, —OC(═O)SR²²², —SC(═O)OR²²², or —SC(═O)NR²²²R³³³substituents; R², R^(2a), R³, R^(3a), R²²², R^(222a), R³³³, R^(333a),R²¹, R^(21a), R³¹, R²²²¹, R^(2221a), R³³³¹, and R^(3331a) are eachindependently C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, orhetaryl-C₂₋₁₀alkynyl, any of which is optionaly substituted by one ormore independent G¹³ substituents; or in the case of—NR²R³(R^(2a))_(j1)or —NR²¹R³¹(R^(21a))_(j3) or—NR²²²R³³³(R^(222a))_(j1a) or —NR²²²R³³³(R^(222a))_(j2a) or—NR²²²¹R^(3331(R) ^(2221a))_(j3a) R² and R³, or R²¹and R³¹, or R²²² andR³³³, or R³³³¹, or R²²²¹and R³³³¹, respectfuly, are optionaly takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring, wherein said ring isoptionaly substituted by one or more independent G¹⁴ substituents andwherein said ring optionaly includes one or more independent heteroatomsother than the nitrogen to which R² and R³, or R²²² and R³³³, or R²²²and R³³³¹, are attached; G¹³ and G¹⁴ are each independently aC₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, orhetaryl-C₂₋₁₀alkynyl, any of which is optionaly substituted with one ormore independent halo, —CF₃, —OCF₃, —OR⁷⁷, —NR⁷⁷R⁸⁷, —C(O)R⁷⁷, —CO₂R⁷⁷,—CONR⁷⁷R⁸⁷, —NO₂, —CN, —S(O),_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷, —NR⁷⁷C(═O)R⁸⁷,—NR⁷⁷C(═O)OR⁸⁷, —NR⁷⁷C(═O)NR⁸⁷R^(77a), —NR⁷⁷S(O),_(j5a)R⁸⁷, —C(═S)OR⁷⁷,—C(═O)SR⁷⁷, —NR⁷⁷C(═NR⁸⁷)NR^(77a)R^(87a), —NR⁷⁷C(═NR⁸⁷)OR^(77a),—NR⁷⁷C(═NR⁸⁷)SR^(77a), —OC(═O )OR⁷⁷, —OC(═O)NR⁷⁷R⁸⁷, —OC(═O )SR⁷⁷,—SC(═O)OR⁷⁷, —P(O)OR⁷⁷OR⁸⁷, or —SC(═O)NR⁷⁷R⁸⁷ substituents; R⁴¹, R⁵¹,R⁷⁷, R^(77a), R⁸⁷, R^(87a), R⁷⁷⁸, and R⁸⁸⁸ are each independentlyC₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₂₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl,C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,diC₁₋₆alkylaminocarbonyl, mono(aryl)aminocarbonyl,di(aryl)aminocarbonyl, C₁₋₁₀alkyl(aryl)aminocarbonyl,monohetarylaminocarbonyl, dihetarylaminocarbonyl, oralkylhetarylaminocarbonyl, any of which is optionaly substituted withone or more independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy,—SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents;or R⁷⁷, R^(77a), R⁸⁷, and R^(87a) are each independentlyaryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl aryl-C₂₋₁₀alkynyl,hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl,mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl, monohetarylaminoalkyl,dihetarylaminoalkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which isoptionaly substituted with one or more independent halo, cyano, nitro,—O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,—CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or—N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; and j1, j1a, j2a, j3, j3a, andj5a are each independently 0, 1, or
 2. 2. The compound or salt of claim1 wherein X¹ is 3-(O)— or 4-(O)—; Y¹is —CH₂—; and n and m are each
 1. 3.The compound or salt of claim 2 wherein R⁴ is aryl, C₀₋₁₀alkyl, orcycloC₃₋₁₀alkyl, any of which is optionaly substituted by one or moreindependent G⁴¹substituents.
 4. The compound or salt of claim 2 whereinR⁴ is phenyl optionaly substituted by one or more independent G⁴¹substituents.
 5. The compound or salt of claim 3 wherein R¹ is aryl,heteroaryl, cycloC₃₋₁₀alkyl, or heterocyclyl, any of which is optionalysubstituted by G¹¹.
 6. The compound or salt of claim 3 wherein R¹ iscycloC₃₋₁₀alkyl which is optionaly substituted by G¹¹.
 7. The compoundor salt of claim 3 wherein R¹is represented by the structural formula:

wherein Z² is a heterocyclyl.
 8. The compound or salt of claim 3 whereinR¹ is represented by the structural formula:

wherein G¹¹ is —C(O)R²¹, —CO₂R²¹, —CONR²¹R³¹, SO₂NR²¹R³¹, —S(O)_(J3)R³¹,C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionaly substituted with one or more independent oxo —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or —OC(═O)NR²²²¹R³³³¹substituents;or G¹¹ is aryl-C₀₋₁₀alkyl or hetaryl-C₀₋₁₀alkyl, any of which isoptionaly substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR³³³¹R^(2221a), —NR²²²¹S(O)_(j3a)R³³³¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or —OC(═O)NR²²²¹R³³³¹substituents.9. The compound or salt of claim 1 wherein R¹ is represented by thestructural formula:

wherein G¹¹ is —C(O)R²¹, —CO₂R²¹, —CONR²¹R³¹, —SO₂NR²¹R³¹,—S(O)_(j3)R³¹, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,heterocyclyl-C₀₋₁₀alkyl, or heterocyclyl-C₂₋₁₀alkenyl, any of which isoptionaly substituted with one or more independent oxo —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—SO₂NR²²²¹R³³³¹, —NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹,—NR²²²¹C(═O)NR²²²¹R³³³¹, —NR²²²¹S(O)_(j3a)R³³³¹,—NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or —OC(═O)NR²²²¹R³³³¹substituents;or aryl-C₀₋₁₀alkyl or hetaryl-C₀₋₁₀alkyl, any of which is optionalysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹, —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —SO₂NR²²²¹R³³³¹,—NR²²²¹C(═O)R³³³¹, —NR²²²¹C(═O)OR³³³¹, —NR²²²¹C(═O)NR²²²¹R³³³¹,—NR²²²¹S(O)_(j3a)R³³³¹, —NR²²²¹C(═NR³³³¹)NR^(2221a)R^(3331a), or—OC(═O)NR²²²¹R³³³¹substituents.
 10. A compound selected from:5-(3-benzyloxy-2-fluoro-phenyl)-7-cyclobutyl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-cyclobutyl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutanone,3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-y]-cyclobutanol,3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-1-methyl-cyclobutanol,3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-1ethyl-cyclobutanol,5-(3-Benzyloxy-phenyl)-7-(3-methylamino-cyclobutyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(3-dimethylamino-cyclobutyl)-imidazo[5,1f][1,2,4]triazin-4-ylamine,7-(3-Azetidin-1-yl-cyclobutyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(3-piperidin-1-yl-cyclobutyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutyl}-acetamide,{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutyl}-carbamicacid methyl ester,1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutyl}-3-methyl-urea,N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutyl}-methanesulfonamide,7-Azetidin-3-yl-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-azetidin-1-yl}-ethanone,{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutyl}-methanol,5-(3-Benzyloxy-phenyl)-7-(3-dimethylaminomethyl-cyclobutyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(3-diethylaminomethyl-cyclobutyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,7-(3-Azetidin-1-ylmethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(3-piperidin-1-ylmethyl-cyclobutyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclobutanecarboxylicacid amide,5-(3-Benzyloxy-phenyl)-7-cyclohexyl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanone,4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanol,4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-1-methyl-cyclohexanol,4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-1-ethyl-cyclohexanol,4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylicacid methyl ester,4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylicacid amide,4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylicacid methylamide,{4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexyl}-methanol,7-(4-Aminomethyl-cyclohexyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(4-dimethylaminomethyl-cyclohexyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,7-(4-Azetidin-1-ylmethyl-cyclohexyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(4-piperidin-1-ylmethyl-cyclohexyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-piperidin-4-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,1-{4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-piperidin-1-yl}-ethanone,5-(3-Benzyloxy-phenyl)-7-cyclopentyl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentanecarboxylicacid methyl ester,3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentanecarboxylicacid amide,3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentanecarboxylicacid methylamide,{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentyl}-methanol,7-(3-Aminomethyl-cyclopentyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5(3-Benzyloxy-phenyl)-7-(3-dimethylaminomethyl-cyclopentyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,7-(3-Azetidin-1-ylmethyl-cyclopentyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5(3-Benzyloxy-phenyl)-7-(3-pyrrolidin-1-ylmethyl-cyclopentyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5(3-Benzyloxy-phenyl)-7-(3-piperidin-1-ylmethyl-cyclopentyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentylmethyl}-acetamide,{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentylmethyl}-carbamicacid methyl ester, 1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentylmethyl}-3-methyl-urea,3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentanone,3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclopentanol,7-(3-Amino-cyclopentyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5(3-Benzyloxy-phenyl)-7-(3-dimethylamino-cyclopentyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,7-(3-Azetidin-1-yl-cyclopentyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5(3-Benzyloxy-phenyl)-7-(3-pyrrolidin-1-yl-cyclopentyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(3-piperidin-1-yl-cyclopentyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-phenyl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzoicacid methyl ester,4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzamide,4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-N-methyl-benzamide,{4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-phenyl}-methanol,7-(4-Aminomethyl-phenyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(4-dimethylaminomethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,N-{4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzyl}-acetamide,{4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzyl}-carbamicacid methyl ester,1-{4-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzyl}-3-methyl-urea,5-(3-Benzyloxy-phenyl)-7-(4-dimethylaminomethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,7-(4-Azetidin-1-ylmethyl-phenyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(4-pyrrolidin-1-ylmethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(4-piperidin-1-ylmethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzoicacid methyl ester,3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzamide,3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-N-methyl-benzamide,{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-phenyl}-methanol,7-(3-Aminomethyl-phenyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzyl}-acetamide,{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzyl}-carbamicacid methyl ester,1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzyl}-3-methyl-urea,N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-benzyl}-methanesulfonamide,5-(3-Benzyloxy-phenyl)-7-(3-dimethylaminomethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(3-diethylaminomethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,7-(3-Azetidin-1-ylmethyl-phenyl)-5-(3-benzyloxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(3-pyrrolidin-1-ylmethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(3-piperidin-1-ylmethyl-phenyl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-pyridin-4-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-oxazol-2-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-thiophen-3-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-thiophen-2-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-thiazol-5-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-thiazol-2-yl-imidazo[5,1-f][1,2,4]triazin-4-ylamine,5-(3-Benzyloxy-phenyl)-7-(1H-imidazol-2-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,or5-(3-Benzyloxy-phenyl)-7-(1H-imidazol-4-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine,or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 12. A method of treating breastcancer, comprising administering a therapeutically effective amount of acompound of claim 10 or a pharmaceutically acceptable salt thereof to apatient in need thereof.